Methods for treating lower urinary tract disorders and the related disorders vulvodynia and vulvar vestibulitis using Cav2.2 subunit calcium channel modulators

ABSTRACT

The invention relates to methods of using Cav2.2 subunit calcium channel modulators to treat painful and non-painful lower urinary tract disorders and the related genitourinary tract disorders vulvodynia and vulvar vestibulitis in normal and spinal cord injured patients.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/453,171, filed Mar. 10, 2003; which is hereby incorporated byreference.

FIELD OF THE INVENTION

The invention relates to methods of using Cav2.2 subunit calcium channelmodulators for treating painful and non-painful lower urinary tractdisorders and the related genitourinary tract disorders vulvodynia andvulvar vestibulitis in normal and spinal cord injured patients.

BACKGROUND OF THE INVENTION

Lower urinary tract disorders affect the quality of life of millions ofmen and women in the United States every year. Disorders of the lowerurinary tract include overactive bladder, prostatitis and prostadynia,interstitial cystitis, benign prostatic hyperplasia, and, in spinal cordinjured patients, spastic bladder.

Overactive bladder is a treatable medical condition that is estimated toaffect 17 to 20 million people in the United States. Current treatmentsfor overactive bladder include medication, diet modification, programsin bladder training, electrical stimulation, and surgery. Currently,antimuscarinics (which are subtypes of the general class ofanticholinergics) are the primary medication used for the treatment ofoveractive bladder. This treatment suffers from limited efficacy andside effects such as dry mouth, dry eyes, dry vagina, palpitations,drowsiness, and constipation, which have proven difficult for someindividuals to tolerate.

Prostatitis and prostadynia are other lower urinary tract disorders thathave been suggested to affect approximately 2–9% of the adult malepopulation (Collins M M, et al., (1998) J. Urology, 159: 1224–1228).Currently, there are no established treatments for prostatitis andprostadynia. Antibiotics are often prescribed, but with little evidenceof efficacy. COX-2 selective inhibitors and α-adrenergic blockers andhave been suggested as treatments, but their efficacy has not beenestablished. Hot sitz baths and anticholinergic drugs have also beenemployed to provide some symptomatic relief.

Interstitial cystitis is another lower urinary tract disorder of unknownetiology that predominantly affects young and middle-aged females,although men and children can also be affected. Past treatments forinterstitial cystitis have included the administration ofantihistamines, sodium pentosanpolysulfate, dimethylsulfoxide, steroids,tricyclic antidepressants and narcotic antagonists, although thesemethods have generally been unsuccessful (Sant, G. R. (1989)Interstitial cystitis: pathophysiology, clinical evaluation andtreatment. Urology Annal 3: 171–196).

Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of theprostate that is very common in men over 40 years of age. Invasivetreatments for BPH include transurethral resection of the prostate,transurethral incision of the prostate, balloon dilation of theprostate, prostatic stents, microwave therapy, laser prostatectomy,transrectal high-intensity focused ultrasound therapy and transurethralneedle ablation of the prostate. However, complications may arisethrough the use of some of these treatments, including retrogradeejaculation, impotence, postoperative urinary tract infection and someurinary incontinence. Non-invasive treatments for BPH include androgendeprivation therapy and the use of 5α-reductase inhibitors andα-adrenergic blockers. However, these treatments have proven onlyminimally to moderately effective for some patients.

Lower urinary tract disorders are particularly problematic forindividuals suffering from spinal cord injury. Following spinal cordinjury, the bladder is usually affected in one of two ways: 1) “spastic”or “reflex” bladder, in which the bladder fills with urine and a reflexautomatically triggers the bladder to empty; or 2) “flaccid” or“non-reflex” bladder, in which the reflexes of the bladder muscles areabsent or slowed. Treatment options for these disorders usually includeintermittent catheterization, indwelling catheterization, or condomcatheterization, but these methods are invasive and frequentlyinconvenient. Urinary sphincter muscles may also be affected by spinalcord injuries, resulting in an inability of urinary sphincter muscles torelax when the bladder contracts (“dyssynergia”). Traditional treatmentsfor dyssynergia include medications that have been somewhat inconsistentin their efficacy or surgery.

In addition to the lower urinary tract disorders described above, therelated genitourinary tract disorders vulvodynia and vulvar vestibulitishave been etiologically and pathologically linked to such lower urinarytract disorders as interstitial cystitis (See Selo-Ojeme et al. (2002)Int. Urogynecol. J. Pelvic Floor Dysfunction 13: 261–2; Metts (2001) Am.Fam. Physician 64: 1199–206; Wesselmann (2001) World J. Urol. 19: 180–5;Parsons et al. (2001) Obstet. Gynecol. 98: 127–32; Heim (2001) Am. Fam.Physician 63: 1535–44; Stewart et al. (1997) J. Reprod. Med. 42: 131–4;Fitzpatrick et al. (1993) Obstet. Gynecol. 81: 860–2). Vulvarvestibulitis syndrome (herein “vulvar vestibulitis”) is a subtype ofvulvodynia. Vulvodynia is a complex gynecologic syndrome characterizedby unexplained vulvar pain, sexual dysfunction, and psychologicaldisability. It has been estimated that 1.5 million American women maysuffer from some degree of vulvodynia. Because of their multiple causes,these disorders can be very difficult to treat. The first-line therapyis typically the treatment of suspected causes by pharmacologictreatment of infections and the discontinued use of suspected irritantsand therapeutic agents that may contribute to the problem. Topicalanesthetics, corticosteroids, and sex hormones may provide somesymptomatic relief. Further treatments may include dietarymodifications, physical therapy and biofeedback, use of topical, oral,or injected therapeutic agents, or surgery. Unfortunately, no singletreatment works in all patients. Moreover, many of these approachesinvolve complex medical procedures, significant costs, and/orundesirable side effects.

Because existing therapies and treatments for lower urinary tractdisorders and the related genitourinary tract disorders vulvodynia andvulvar vestibulitis in normal and spinal cord injured patients areassociated with limitations as described above, new therapies andtreatments are therefore desirable.

SUMMARY OF THE INVENTION

Compositions and methods for treating painful and non-painful lowerurinary tract disorders, and the related genitourinary tract disordersvulvodynia and vulvar vestibulitis in normal and spinal cord injuredpatients, are provided. Compositions of the invention comprise Cav2.2subunit calcium channel modulators and other peptide, non-peptide, andpeptidomimetic drug-like molecules that bind to Cav2.2-containingcalcium channels, as well as pharmaceutically acceptable,pharmacologically active salts, esters, amides, prodrugs, activemetabolites, and other derivatives thereof.

The compositions are administered in therapeutically effective amountsto a patient in need thereof for treating painful and non-painful lowerurinary tract disorders and the related genitourinary tract disordersvulvodynia and vulvar vestibulitis in normal and spinal cord injuredpatients. It is recognized that the compositions may be administered byany means of administration as long as an effective amount for thetreatment of painful and non-painful symptoms associated with lowerurinary tract disorders and the related genitourinary tract disordersvulvodynia and vulvar vestibulitis in normal and spinal cord injuredpatients is delivered. The compositions may be formulated, for example,for sustained, continuous, or as-needed administration.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1. FIG. 1 depicts intermicturition intervals before (Sal) and after(remaining groups) bladder hyperactivity caused by continuousintravesical dilute acetic acid infusion. ω-Conotoxin MVIIA wasadministered intrathecally at increasing doses, and data is representedas Mean (± SEM) intermicturition intervals in minutes.

FIG. 2. FIG. 2 depicts bladder capacity before (Sal) and after(remaining groups) bladder hyperactivity caused by continuousintravesical dilute acetic acid infusion. ω-Conotoxin MVIIA wasadministered intrathecally at increasing doses and data has beennormalized to irritation control values (AA/Veh3) and is represented asMean (± SEM).

FIG. 3. FIG. 3A depicts HVA calcium channel currents in dorsal rootganglion neurons innervating the urinary bladder induced by depolarizingpulses (−80 to 0 mV) before (control) and after application ofOmega-conotoxin GVIA. FIG. 3B depicts changes in peak HVA calciumcurrents in bladder afferents following application of Omega-conotoxinGVIA expressed as percentage of control peak calcium current amplitude.

DETAILED DESCRIPTION OF THE INVENTION

Overview and Definitions

The present invention provides compositions and methods for treatingpainful and non-painful lower urinary tract disorders and the relatedgenitourinary tract disorders vulvodynia and vulvar vestibulitis innormal and spinal cord injured patients. The lower urinary tractdisorders of the present invention include, but are not limited to suchdisorders as painful and non-painful overactive bladder, prostatitis andprostadynia, interstitial cystitis, benign prostatic hyperplasia, and,in spinal cord injured patients, and spastic bladder. The compositionscomprise a therapeutically effective dose of a Cav2.2 subunit calciumchannel modulator. The methods are accomplished by administering, forexample, various compositions and formulations that contain quantitiesof a Cav2.2 subunit calcium channel modulator and other peptide,non-peptide, and peptidomimetic drug-like molecules that bind toCav2.2-containing calcium channels.

Before describing the present invention in detail, it is to beunderstood that this invention is not limited to specific active agents,dosage forms, dosing regimens, or the like, as such may vary. It is alsoto be understood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting.

It must be noted that as used in this specification and the appendedembodiments, the singular forms “a,” “an,” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “an active agent” or “a pharmacologically activeagent” includes a single active agent as well as two or more differentactive agents in combination, reference to “a carrier” includes mixturesof two or more carriers as well as a single carrier, and the like.

By “non-painful” is intended sensations or symptoms including mild orgeneral discomfort that a patient subjectively describes as notproducing or resulting in pain.

By “painful” is intended sensations or symptoms that a patientsubjectively describes as producing or resulting in pain.

By “lower urinary tract” is intended all parts of the urinary systemexcept the kidneys. By “lower urinary tract disorder” is intended anydisorder involving the lower urinary tract, including but not limited tooveractive bladder, prostatitis, interstitial cystitis, benign prostatichyperplasia, and spastic and flaccid bladder. By “non-painful lowerurinary tract disorder” is intended any lower urinary tract disorderinvolving sensations or symptoms, including mild or general discomfort,that a patient subjectively describes as not producing or resulting inpain. By “painful lower urinary tract disorder” is intended any lowerurinary tract disorder involving sensations or symptoms that a patientsubjectively describes as producing or resulting in pain.

By “bladder disorder” is intended any condition involving the urinarybladder. By “non-painful bladder disorder” is intended any bladderdisorder involving sensations or symptoms, including mild or generaldiscomfort, that a patient subjectively describes as not producing orresulting in pain. By “painful bladder disorder” is intended any bladderdisorder involving sensations or symptoms that a patient subjectivelydescribes as producing or resulting in pain.

By “overactive bladder” is intended any form of lower urinary tractdisorder characterized by increased frequency of micturition or thedesire to void, whether complete or episodic, and where loss ofvoluntary control ranges from partial to total and whether there is lossof urine (incontinence) or not. By “painful overactive bladder” isintended any form of overactive bladder, as defined above, involvingsensations or symptoms that a patient subjectively describes asproducing or resulting in pain. By “non-painful overactive bladder” isintended any form of overactive bladder, as defined above, involvingsensations or symptoms, including mild or general discomfort, that apatient subjectively describes as not producing or resulting in pain.Non-painful symptoms can include, but are not limited to, urinaryurgency, incontinence, urge incontinence, stress incontinence, urinaryfrequency, and nocturia.

“OAB wet” is used herein to describe overactive bladder in patients withincontinence, while “OAB dry” is used herein to describe overactivebladder in patients without incontinence.

By “urinary urgency” is intended sudden strong urges to urinate withlittle or no chance to postpone the urination. By “incontinence” ismeant the inability to control excretory functions, including urination(urinary incontinence). By “urge incontinence” or “urinary urgeincontinence” is intended the involuntary loss of urine associated withan abrupt and strong desire to void. By “stress incontinence” or“urinary stress incontinence” is intended a medical condition in whichurine leaks when a person coughs, sneezes, laughs, exercises, liftsheavy objects, or does anything that puts pressure on the bladder. By“urinary frequency” is intended urinating more frequently than thepatient desires. As there is considerable interpersonal variation in thenumber of times in a day that an individual would normally expect tourinate, “more frequently than the patient desires” is further definedas a greater number of times per day than that patient's historicalbaseline. “Historical baseline” is further defined as the median numberof times the patient urinated per day during a normal or desirable timeperiod. By “nocturia” is intended being awakened from sleep to urinatemore frequently than the patient desires.

By “neurogenic bladder” or “neurogenic overactive bladder” is intendedoveractive bladder as described further herein that occurs as the resultof neurological damage due to disorders including but not limited tostroke, Parkinson's disease, diabetes, multiple sclerosis, peripheralneuropathy, or spinal cord lesions.

By “detrusor hyperreflexia” is intended a condition characterized byuninhibited detrusor, wherein the patient has some sort of neurologicimpairment. By “detrusor instability” or “unstable detrusor” is intendedconditions where there is no neurologic abnormality.

By “prostatitis” is intended any type of disorder associated with aninflammation of the prostate, including chronic bacterial prostatitisand chronic non-bacterial prostatitis. By “non-painful prostatitis” isintended prostatitis involving sensations or symptoms, including mild orgeneral discomfort, that a patient subjectively describes as notproducing or resulting in pain. By “painful prostatitis” is intendedprostatitis involving sensations or symptoms that a patient subjectivelydescribes as producing or resulting in pain.

“Chronic bacterial prostatitis” is used in its conventional sense torefer to a disorder associated with symptoms that include inflammationof the prostate and positive bacterial cultures of urine and prostaticsecretions. “Chronic non-bacterial prostatitis” is used in itsconventional sense to refer to a disorder associated with symptoms thatinclude inflammation of the prostate and negative bacterial cultures ofurine and prostatic secretions. “Prostadynia” is used in itsconventional sense to refer to a disorder generally associated withpainful symptoms of chronic non-bacterial prostatitis as defined above,without inflammation of the prostate. “Interstitial cystitis” is used inits conventional sense to refer to a disorder associated with symptomsthat include irritative voiding symptoms, urinary frequency, urgency,nocturia, and suprapubic or pelvic pain related to and relieved byvoiding.

“Benign prostatic hyperplasia” is used in its conventional sense torefer to a disorder associated with benign enlargement of the prostategland.

“Spastic bladder” or “reflex bladder” is used in its conventional senseto refer to a condition following spinal cord injury in which bladderemptying has become unpredictable.

“Flaccid bladder” or “non-reflex bladder” is used in its conventionalsense to refer to a condition following spinal cord injury in which thereflexes of the bladder muscles are absent or slowed.

“Dyssynergia” is used in its conventional sense to refer to a conditionfollowing spinal cord injury in which patients characterized by aninability of urinary sphincter muscles to relax when the bladdercontracts.

“Vulvodynia” is used in its conventional sense to refer to a conditioncharacterized by gynecologic syndrome characterized by unexplainedvulvar pain, sexual dysfunction, and psychological disability.

“Vulvar vestibulitis” (also known as “vulvar vestibulitis syndrome,”“focal vulvitis,” and “vestibular adenitis”) is used in its conventionalsense to refer to a condition that is a subtype of vulvodyniacharacterized by: 1) pain on vestibular touch or attempted vaginalentry; 2) tenderness to Q-tip pressure localized within the vulvarvestibule; 3) physical findings confined to vestibular erythema ofvarious degrees; and 4) an exclusion of other causes for vestibularerythema and tenderness, such as candidiasis (yeast infections) orherpes infections. Other symptoms may include itching, swelling andexcoriation.

The terms “active agent” and “pharmacologically active agent” are usedinterchangeably herein to refer to a chemical compound that induces adesired effect, i.e., in this case, treatment of painful and non-painfullower urinary tract disorders, and the related genitourinary tractdisorders vulvodynia and vulvar vestibulitis, in normal and spinal cordinjured patients. The primary active agents herein are compounds thatmodulate Cav2.2 calcium channel subunits. In addition, a combinationtherapy wherein a compound that modulates Cav2.2 calcium channelsubunits is administered with one or more additional active agents isalso within the scope of the present invention. Such combination therapymay be carried out by administration of the different active agents in asingle composition, by concurrent administration of the different activeagents in different compositions, or by sequential administration of thedifferent active agents. Included are derivatives and analogs of thosecompounds or classes of compounds specifically mentioned that alsoinduce the desired effect.

The term “Cav2.2 subunit calcium channel modulator” as used herein isintended an agent that is capable of binding to the Cav2.2 subunit of acalcium channel to produce a physiological effect, such as opening,closing, blocking, up-regulating expression, or down-regulatingexpression of the channel. Unless otherwise indicated, the term “Cav2.2subunit calcium channel modulator” is intended to include amino acidcompounds, peptide, nonpeptide, peptidomimetic, small molecular weightorganic compounds, and other compounds that modulate or interact withthe Cav2.2 subunit of a calcium channel (e.g., a binding event) orproteins associated with the Cav2.2 subunit of a calcium channel (e.g.,a binding event) such as anchor proteins, as well as salts, esters,amides, prodrugs, active metabolites, and other derivatives thereof.Further, it is understood that any salts, esters, amides, prodrugs,active metabolites or other derivatives are pharmaceutically acceptableas well as pharmacologically active.

The term “peptidomimetic” is used in its conventional sense to refer toa molecule that mimics the biological activity of a peptide but is nolonger peptidic in chemical nature, including molecules that lack amidebonds between amino acids, as well as pseudo-peptides, semi-peptides andpeptoids. Peptidomimetics according to this invention provide a spatialarrangement of reactive chemical moieties that closely resembles thethree-dimensional arrangement of active groups in the peptide on whichthe peptidomimetic is based. As a result of this similar active-sitegeometry, the peptidomimetic has effects on biological systems that aresimilar to the biological activity of the peptide.

The terms “treating” and “treatment” as used herein refer to relievingthe painful or non-painful symptoms or other clinically observedsequelae for clinically diagnosed disorders as described herein,including disorders associated with lower urinary tract, and the relatedgenitourinary tract disorders vulvodynia and vulvar vestibulitis, innormal and spinal cord injured patients.

By an “effective” amount or a “therapeutically effective amount” of adrug or pharmacologically active agent is meant a nontoxic butsufficient amount of the drug or agent to provide the desired effect,i.e., relieving the painful and non-painful symptoms associated withlower urinary tract disorders, and the related genitourinary tractdisorders vulvodynia and vulvar vestibulitis, in normal and spinal cordinjured patients, as explained above. It is recognized that theeffective amount of a drug or pharmacologically active agent will varydepending on the route of administration, the selected compound, and thespecies to which the drug or pharmacologically active agent isadministered. It is also recognized that one of skill in the art willdetermine appropriate effective amounts by taking into account suchfactors as metabolism, bioavailability, and other factors that affectplasma levels of a drug or pharmacologically active agent followingadministration within the unit dose ranges disclosed further herein fordifferent routes of administration.

By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptableacid addition salt,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the other components of the composition in which it iscontained. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” derivative or metabolite, refers to aderivative or metabolite having the same type of pharmacologicalactivity as the parent compound. When the term “pharmaceuticallyacceptable” is used to refer to a derivative (e.g., a salt or an analog)of an active agent, it is to be understood that the compound ispharmacologically active as well, i.e., therapeutically effective fortreating painful and non-painful lower urinary tract disorders, and therelated genitourinary tract disorders vulvodynia and vulvarvestibulitis, in normal and spinal cord injured patients.

By “continuous” dosing is meant the chronic administration of a selectedactive agent. By “as-needed” dosing, also known as “pro re nata” “prn”dosing, and “on demand” dosing or administration is meant theadministration of a single dose of the active agent at some time priorto commencement of an activity wherein suppression of the painful andnon-painful symptoms of a lower urinary tract disorder, and the relatedgenitourinary tract disorders vulvodynia and vulvar vestibulitis, innormal and spinal cord injured patients, would be desirable.Administration can be immediately prior to such an activity, includingabout 0 minutes, about 10 minutes, about 20 minutes, about 30 minutes,about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5hours, about 6 hours, about 7 hours, about 8 hours, about 9 hours, orabout 10 hours prior to such an activity, depending on the formulation.

By “short-term” is intended any period of time up to and including about8 hours, about 7 hours, about 6 hours, about 5 hours, about 4 hours,about 3 hours, about 2 hours, about 1 hour, about 40 minutes, about 20minutes, or about 10 minutes after drug administration.

By “rapid-offset” is intended any period of time up to and includingabout 8 hours, about 7 hours, about 6 hours, about 5 hours, about 4hours, about 3 hours, about 2 hours, about 1 hour, about 40 minutes,about 20 minutes, or about 10 minutes after drug administration.

The term “controlled release” is intended to refer to anydrug-containing formulation in which release of the drug is notimmediate, i.e., with a “controlled release” formulation, oraladministration does not result in immediate release of the drug into anabsorption pool. The term is used interchangeably with “non-immediaterelease” as defined in Remington: The Science and Practice of Pharmacy,Twentieth Ed. (Philadelphia, Pa.: Lippincott Williams & Wilkins, 2000).

The “absorption pool” represents a solution of the drug administered ata particular absorption site, and k_(r), k_(a), and k_(e) arefirst-order rate constants for: 1) release of the drug from theformulation; 2) absorption; and 3) elimination, respectively. Forimmediate release dosage forms, the rate constant for drug release k_(r)is far greater than the absorption rate constant k_(a). For controlledrelease formulations, the opposite is true, i.e., k_(r)<<<k_(a), suchthat the rate of release of drug from the dosage form is therate-limiting step in the delivery of the drug to the target area. Theterm “controlled release” as used herein includes any nonimmediaterelease formulation, including but not limited to sustained release,delayed release and pulsatile release formulations.

The term “sustained release” is used in its conventional sense to referto a drug formulation that provides for gradual release of a drug overan extended period of time, and that preferably, although notnecessarily, results in substantially constant blood levels of a drugover an extended time period such as up to about 72 hours, about 66hours, about 60 hours, about 54 hours, about 48 hours, about 42 hours,about 36 hours, about 30 hours, about 24 hours, about 18 hours, about 12hours, about 10 hours, about 8 hours, about 7 hours, about 6 hours,about 5 hours, about 4 hours, about 3 hours, about 2 hours, or about 1hour after drug administration.

The term “delayed release” is used in its conventional sense to refer toa drug formulation that provides for an initial release of the drugafter some delay following drug administration and that preferably,although not necessarily, includes a delay of up to about 10 minutes,about 20 minutes, about 30 minutes, about 1 hour, about 2 hours, about 3hours, about 4 hours, about 5 hours, about 6 hours, about 7 hours, about8 hours, about 9 hours, about 10 hours, about 11 hours, or about 12hours.

The term “pulsatile release” is used in its conventional sense to referto a drug formulation that provides release of the drug in such a way asto produce pulsed plasma profiles of the drug after drug administration.The term “immediate release” is used in its conventional sense to referto a drug formulation that provides for release of the drug immediatelyafter drug administration.

The term “immediate release” is used in its conventional sense to referto a drug formulation that provides for release of the drug immediatelyafter drug administration.

By the term “transdermal” drug delivery is meant delivery by passage ofa drug through the skin or mucosal tissue and into the bloodstream.

The term “topical administration” is used in its conventional sense tomean delivery of a topical drug or pharmacologically active agent to theskin or mucosa.

The term “oral administration” is used in its conventional sense to meandelivery of a drug through the mouth and ingestion through the stomachand digestive tract.

The term “inhalation administration” is used in its conventional senseto mean delivery of an aerosolized form of the drug by passage throughthe nose or mouth during inhalation and passage of the drug through thewalls of the lungs.

The term “intravesical administration” is used in its conventional senseto mean delivery of a drug directly into the bladder.

By the term “parenteral” drug delivery is meant delivery by passage of adrug into the blood stream without first having to pass through thealimentary canal, or digestive tract. Parenteral drug delivery may be“subcutaneous,” referring to delivery of a drug by administration underthe skin. Another form of parenteral drug delivery is “intramuscular,”referring to delivery of a drug by administration into muscle tissue.Another form of parenteral drug delivery is “intradermal,” referring todelivery of a drug by administration into the skin. An additional formof parenteral drug delivery is “intravenous,” referring to delivery of adrug by administration into a vein. An additional form of parenteraldrug delivery is “intra-arterial,” referring to delivery of a drug byadministration into an artery. Another form of parenteral drug deliveryis “transdermal,” referring to delivery of a drug by passage of the drugthrough the skin and into the bloodstream. Another form of parenteraldrug delivery is “intrathecal,” referring to delivery of a drug directlyinto the into the intrathecal space (where fluid flows around the spinalcord).

Still another form of parenteral drug delivery is “transmucosal,”referring to administration of a drug to the mucosal surface of anindividual so that the drug passes through the mucosal tissue and intothe individual's blood stream. Transmucosal drug delivery may be“buccal” or “transbuccal,” referring to delivery of a drug by passagethrough an individual's buccal mucosa and into the bloodstream. Anotherform of transmucosal drug delivery herein is “lingual” drug delivery,which refers to delivery of a drug by passage of a drug through anindividual's lingual mucosa and into the bloodstream. Another form oftransmucosal drug delivery herein is “sublingual” drug delivery, whichrefers to delivery of a drug by passage of a drug through anindividual's sublingual mucosa and into the bloodstream. Another form oftransmucosal drug delivery is “nasal” or “intranasal” drug delivery,referring to delivery of a drug through an individual's nasal mucosa andinto the bloodstream. An additional form of transmucosal drug deliveryherein is “rectal” or “transrectal” drug delivery, referring to deliveryof a drug by passage of a drug through an individual's rectal mucosa andinto the bloodstream. Another form of transmucosal drug delivery is“urethral” or “transurethral” delivery, referring to delivery of thedrug into the urethra such that the drug contacts and passes through thewall of the urethra. An additional form of transmucosal drug delivery is“vaginal” or “transvaginal” delivery, referring to delivery of a drug bypassage of a drug through an individual's vaginal mucosa and into thebloodstream. An additional form of transmucosal drug delivery is“perivaginal” delivery, referring to delivery of a drug through thevaginolabial tissue into the bloodstream.

In order to carry out the method of the invention, a selected activeagent is administered to a patient suffering from a painful ornon-painful lower urinary tract disorder, and the related genitourinarytract disorders vulvodynia and vulvar vestibulitis, in normal and spinalcord injured patients. A therapeutically effective amount of the activeagent may be administered orally, intravenously, subcutaneously,transmucosally (including buccally, sublingually, transurethrally, andrectally), topically, transdermally, by inhalation, intravesically,intrathecally or using any other route of administration.

Lower Urinary Tract Disorders

Lower urinary tract disorders affect the quality of life of millions ofmen and women in the United States every year. While the kidneys filterblood and produce urine, the lower urinary tract is concerned withstorage and elimination of this waste liquid and includes all otherparts of the urinary tract except the kidneys. Generally, the lowerurinary tract includes the ureters, the urinary bladder, and theurethra. Disorders of the lower urinary tract include painful andnon-painful overactive bladder, prostatitis and prostadynia,interstitial cystitis, benign prostatic hyperplasia, and, in spinal cordinjured patients, spastic bladder and flaccid bladder.

Overactive bladder is a treatable medical condition that is estimated toaffect 17 to 20 million people in the United States. Symptoms ofoveractive bladder include urinary frequency, urgency, nocturia (thedisturbance of nighttime sleep because of the need to urinate) and urgeincontinence (accidental loss of urine) due to a sudden and unstoppableneed to urinate. As opposed to stress incontinence, in which loss ofurine is associated with physical actions such as coughing, sneezing,exercising, or the like, urge incontinence is usually associated with anoveractive detrusor muscle (the smooth muscle of the bladder whichcontracts and causes it to empty).

There is no single etiology for overactive bladder. Neurogenicoveractive bladder (or neurogenic bladder) occurs as the result ofneurological damage due to disorders such as stroke, Parkinson'sdisease, diabetes, multiple sclerosis, peripheral neuropathy, or spinalcord lesions. In these cases, the overactivity of the detrusor muscle istermed detrusor hyperreflexia. By contrast, non-neurogenic overactivebladder can result from non-neurological abnormalities including bladderstones, muscle disease, urinary tract infection or drug side effects.

Due to the enormous complexity of micturition (the act of urination) theexact mechanism causing overactive bladder is unknown. Overactivebladder may result from hypersensitivity of sensory neurons of theurinary bladder, arising from various factors including inflammatoryconditions, hormonal imbalances, and prostate hypertrophy. Destructionof the sensory nerve fibers, either from a crushing injury to the sacralregion of the spinal cord, or from a disease that causes damage to thedorsal root fibers as they enter the spinal cord may also lead tooveractive bladder. In addition, damage to the spinal cord or brain stemcausing interruption of transmitted signals may lead to abnormalities inmicturition. Therefore, both peripheral and central mechanisms may beinvolved in mediating the altered activity in overactive bladder.

In spite of the uncertainty regarding whether central or peripheralmechanisms, or both, are involved in overactive bladder, many proposedmechanisms implicate neurons and pathways that mediate non-painfulvisceral sensation. Pain is the perception of an aversive or unpleasantsensation and may arise through a variety of proposed mechanisms. Thesemechanisms include activation of specialized sensory receptors thatprovide information about tissue damage (nociceptive pain), or throughnerve damage from diseases such as diabetes, trauma or toxic doses ofdrugs (neuropathic pain) (See, e.g., A. I. Basbaum and T. M. Jessell(2000) The perception of pain. In Principles of Neural Science, 4th.ed.; Benevento et al. (2002) Physical Therapy Journal 82:601–12).Nociception may give rise to pain, but not all stimuli that activatenociceptors are experienced as pain (A. I. Basbaum and T. M. Jessell(2000) The perception of pain. In Principles of Neural Science, 4th.ed.). Somatosensory information from the bladder is relayed bynociceptive Aδ and C fibers that enter the spinal cord via the dorsalroot ganglion (DRG) and project to the brainstem and thalamus via secondor third order neurons (Andersson (2002) Urology 59:18–24; Andersson(2002) Urology 59:43–50; Morrison, J., Steers, W. D., Brading, A., Blok,B., Fry, C., de Groat, W. C., Kakizaki, H., Levin, R., and Thor, K. B.,“Basic Urological Sciences” In: Incontinence (vol. 2) Abrams, P. Khoury,S., and Wein, A. (Eds.) Health Publications, Ltd., PlymbridgeDitributors, Ltd., Plymouth, UK., (2002). A number of different subtypesof sensory afferent neurons may be involved in neurotransmission fromthe lower urinary tract. These may be classified as, but not limited to,small diameter, medium diameter, large diameter, myelinated,unmyelinated, sacral, lumbar, peptidergic, non-peptidergic, IB4positive, IB4 negative, C fiber, Aδ fiber, high threshold or lowthreshold neurons. Nociceptive input to the DRG is thought to beconveyed to the brain along several ascending pathways, including thespinothalamic, spinoreticular, spinomesencephalic, spinocervical, and insome cases dorsal column/medial lemniscal tracts (A. I. Basbaum and T.M. Jessell (2000) The perception of pain. In Principles of NeuralScience, 4th. ed.). Central mechanisms, which are not fully understood,are thought to convert some, but not all, nociceptive information intopainful sensory perception (A. I. Basbaum and T. M. Jessell (2000) Theperception of pain. In Principles of Neural Science, 4th. ed.). Althoughmany compounds have been explored as treatments for disorders involvingpain of the bladder or other pelvic visceral organs, relatively littlework has been directed toward treatment of non-painful sensory symptomsassociated with bladder disorders such as overactive bladder.

The compounds of the present invention are useful in the treatment ofboth painful and non-painful overactive bladder. Current treatments foroveractive bladder include medication, diet modification, programs inbladder training, electrical stimulation, and surgery. Currently,antimuscarinics (which are subtypes of the general class ofanticholinergics) are the primary medication used for the treatment ofoveractive bladder. This treatment suffers from limited efficacy andside effects such as dry mouth, dry eyes, dry vagina, palpitations,drowsiness, and constipation, which have proven difficult for someindividuals to tolerate. Therefore, the compounds of the presentinvention meet an existing need for new treatments for both painful andnon-painful overactive bladder.

Overactive bladder (or OAB) can occur with or without incontinence. Inrecent years, it has been recognized among those of skill in the artthat the cardinal symptom of OAB is urgency without regard to anydemonstrable loss of urine. For example, a recent study examined theimpact of all OAB symptoms on the quality of life of a community-basedsample of the United States population. (Liberman et al. (2001) Urology57: 1044–1050). This study demonstrated that individuals suffering fromOAB without any demonstrable loss of urine have an impaired quality oflife when compared with controls. Additionally, individuals with urgencyalone have an impaired quality of life compared with controls.

Although urgency is now believed to be the primary symptom of OAB, todate it has not been evaluated in a quantified way in clinical studies.Corresponding to this new understanding of OAB, however, the terms OABWet (with incontinence) and OAB Dry (without incontinence) have beenproposed to describe these different patient populations (see, e.g.,WO03/051354). The prevalence of OAB Wet and OAB Dry is reported to besimilar in men and women, with a prevalence rate in the United States of16.6% (Stewart et al., “Prevalence of Overactive Bladder in the UnitedStates: Results from the NOBLE Program,” Abstract Presented at theSecond International Consultation on Incontinence, July 2001, Paris,France). In particular, the compounds of the present invention areuseful in the treatment of OAB Wet and OAB Dry.

Prostatitis and prostadynia are other lower urinary tract disorders thathave been suggested to affect approximately 2–9% of the adult malepopulation (Collins M M, et al., (1998) “How common is prostatitis? Anational survey of physician visits,” Journal of Urology, 159:1224–1228). Prostatitis is associated with an inflammation of theprostate, and may be subdivided into chronic bacterial prostatitis andchronic non-bacterial prostatitis. Chronic bacterial prostatitis isthought to arise from bacterial infection and is generally associatedwith such symptoms as inflammation of the prostate, the presence ofwhite blood cells in prostatic fluid, and/or pain. Chronic non-bacterialprostatitis is an inflammatory and painful condition of unknown etiologycharacterized by excessive inflammatory cells in prostatic secretionsdespite a lack of documented urinary tract infections, and negativebacterial cultures of urine and prostatic secretions. Prostadynia(chronic pelvic pain syndrome) is a condition associated with thepainful symptoms of chronic non-bacterial prostatitis without aninflammation of the prostate.

The compounds of the present invention are useful for the treatment ofprostatitis and prostadynia. Currently, there are no establishedtreatments for prostatitis and prostadynia. Antibiotics are oftenprescribed, but with little evidence of efficacy. COX-2 selectiveinhibitors and α-adrenergic blockers and have been suggested astreatments, but their efficacy has not been established. Hot sitz bathsand anticholinergic drugs have also been employed to provide somesymptomatic relief. Therefore, the compounds of the present inventionmeet an existing need for new treatments for prostatitis andprostadynia.

Interstitial cystitis is another lower urinary tract disorder of unknownetiology that predominantly affects young and middle-aged females,although men and children can also be affected. Symptoms of interstitialcystitis may include irritative voiding symptoms, urinary frequency,urgency, nocturia and suprapubic or pelvic pain related to and relievedby voiding. Many interstitial cystitis patients also experienceheadaches as well as gastrointestinal and skin problems. In some extremecases, interstitial cystitis may also be associated with ulcers or scarsof the bladder.

The compounds of the present invention are useful for the treatment ofinterstitial cystitis. Past treatments for interstitial cystitis haveincluded the administration of antihistamines, sodiumpentosanpolysulfate, dimethylsulfoxide, steroids, tricyclicantidepressants and narcotic antagonists, although these methods havegenerally been unsuccessful (Sant, G. R. (1989) Interstitial cystitis:pathophysiology, clinical evaluation and treatment. Urology Annal 3:171–196). Therefore, the compounds of the present invention meet anexisting need for new treatments for interstitial cystitis.

Benign prostatic hyperplasia (BPH) is a non-malignant enlargement of theprostate that is very common in men over 40 years of age. BPH is thoughtto be due to excessive cellular growth of both glandular and stromalelements of the prostate. Symptoms of BPH include urinary frequency,urge incontinence, nocturia, and reduced urinary force and speed offlow.

The compounds of the present invention are useful for the treatment ofBPH. Invasive treatments for BPH include transurethral resection of theprostate, transurethral incision of the prostate, balloon dilation ofthe prostate, prostatic stents, microwave therapy, laser prostatectomy,transrectal high-intensity focused ultrasound therapy and transurethralneedle ablation of the prostate. However, complications may arisethrough the use of some of these treatments, including retrogradeejaculation, impotence, postoperative urinary tract infection and someurinary incontinence. Non-invasive treatments for BPH include androgendeprivation therapy and the use of 5α-reductase inhibitors andα-adrenergic blockers. However, these treatments have proven onlyminimally to moderately effective for some patients. Therefore, thecompounds of the present invention meet an existing need for newtreatments for BPH.

The compounds of the present invention are also useful for treatinglower urinary tract disorders in spinal cord injured patients. Afterspinal cord injury, the kidneys continue to make urine, and urine cancontinue to flow through the ureters and urethra because they are thesubject of involuntary neural and muscular control, with the exceptionof conditions where bladder to smooth muscle urethra dyssenergia ispresent. By contrast, bladder and sphincter muscles are also subject tovoluntary neural and muscular control, meaning that descending inputfrom the brain through the spinal cord drives bladder and sphinctermuscles to completely empty the bladder. Following spinal cord injury,such descending input may be disrupted such that individuals may nolonger have voluntary control of their bladder and sphincter muscles.Spinal cord injuries can also disrupt sensory signals that ascend to thebrain, preventing such individuals from being able to feel the urge tourinate when their bladder is full.

Following spinal cord injury, the bladder is usually affected in one oftwo ways. The first is a condition called “spastic” or “reflex” bladder,in which the bladder fills with urine and a reflex automaticallytriggers the bladder to empty. This usually occurs when the injury isabove the T12 level. Individuals with spastic bladder are unable todetermine when, or if, the bladder will empty. The second is “flaccid”or “non-reflex” bladder, in which the reflexes of the bladder musclesare absent or slowed. This usually occurs when the injury is below theT12/L1 level. Individuals with flaccid bladder may experienceover-distended or stretched bladders and “reflux” of urine through theureters into the kidneys. Treatment options for these disorders usuallyinclude intermittent catheterization, indwelling catheterization, orcondom catheterization, but these methods are invasive and frequentlyinconvenient. Therefore, the compounds of the present invention meet anexisting need for new treatments for spastic bladder and flaccidbladder.

Urinary sphincter muscles may also be affected by spinal cord injuries,resulting in a condition known as “dyssynergia.” Dyssynergia involves aninability of urinary sphincter muscles to relax when the bladdercontracts, including active contraction in response to bladdercontraction, which prevents urine from flowing through the urethra andresults in the incomplete emptying of the bladder and “reflux” of urineinto the kidneys. Traditional treatments for dyssynergia includemedications that have been somewhat inconsistent in their efficacy orsurgery. Therefore, the compounds of the present invention meet anexisting need for new treatments for dyssynergia.

Peripheral vs. Central Effects

The mammalian nervous system comprises a central nervous system (CNS,comprising the brain and spinal cord) and a peripheral nervous system(PNS, comprising sympathetic, parasympathetic, sensory, motor, andenteric neurons outside of the brain and spinal cord). Where an activeagent according to the present invention is intended to act centrally(i.e., exert its effects via action on neurons in the CNS), the activeagent must either be administered directly into the CNS or be capable ofbypassing or crossing the blood-brain barrier. The blood-brain barrieris a capillary wall structure that effectively screens out all butselected categories of substances present in the blood, preventing theirpassage into the CNS. The unique morphologic characteristics of thebrain capillaries that make up the blood-brain barrier are: 1)epithelial-like high resistance tight junctions which literally cementall endothelia of brain capillaries together within the blood-brainbarrier regions of the CNS; and 2) scanty pinocytosis ortransendothelial channels, which are abundant in endothelia ofperipheral organs. Due to the unique characteristics of the blood-brainbarrier, many hydrophilic drugs and peptides that readily gain access toother tissues in the body are barred from entry into the brain or theirrates of entry are very low.

The blood-brain barrier can be bypassed effectively by direct infusionof the active agent into the brain, or by intranasal administration orinhalation of formulations suitable for uptake and retrograde transportof the active agent by olfactory neurons.

The most common procedure for administration directly into the CNS isthe implantation of a catheter into the ventricular system orintrathecal space. Alternatively, the active agent can be modified toenhance its transport across the blood-brain barrier. This generallyrequires some solubility of the drug in lipids, or other appropriatemodification known to one of skill in the art. For example, the activeagent may be truncated, derivatized, latentiated (converted from ahydrophilic drug into a lipid-soluble drug), conjugated to a lipophilicmoiety or to a substance that is actively transported across theblood-brain barrier, or modified using standard means known to thoseskilled in the art. See, for example, Pardridge, Endocrine Reviews 7:314–330 (1986) and U.S. Pat. No. 4,801,575.

Where an active agent according to the present invention is intended toact exclusively peripherally (i.e., exert its effects via action eitheron neurons in the PNS or directly on target tissues), it may bedesirable to modify the compounds of the present invention such thatthey will not pass the blood-brain barrier. The principle of blood-brainbarrier permeability can therefore be used to design active agents withselective potency for peripheral targets. Generally, a lipid-insolubledrug will not cross the blood-brain barrier, and will not produceeffects on the CNS. A basic drug that acts on the nervous system may bealtered to produce a selective peripheral effect by quaternization ofthe drug, which decreases its lipid solubility and makes it virtuallyunavailable for transfer to the CNS. For example, the chargedantimuscarinic drug methscopalamine bromide has peripheral effects whilethe uncharged antimuscarinic drug scopolamine acts centrally. One ofskill in the art can select and modify active agents of the presentinvention using well-known standard chemical synthetic techniques to adda lipid impermeable functional group such a quaternary amine, sulfate,carboxylate, phosphate, or sulfonium to prevent transport across theblood-brain barrier. Such modifications are by no means the only way inwhich active agents of the present invention may be modified to beimpermeable to the blood-brain barrier; other well known pharmaceuticaltechniques exist and would be considered to fall within the scope of thepresent invention.

Agents

Compounds useful in the present invention include any active agent asdefined elsewhere herein. Such active agents include, for example, anycompound that binds to the Cav2.2 subunit of a calcium channel.

Voltage gated calcium channels, also known as voltage dependent calciumchannels, are multi-subunit membrane-spanning proteins which permitcontrolled calcium influx from an extracellular environment into theinterior of a cell. Opening and closing (gating) of voltage gatedcalcium channels is controlled by a voltage sensitive region of theprotein containing charged amino acids that move within an electricfield. The movement of these charged groups leads to conformationalchanges in the structure of the channel resulting in conducting(open/activated) or non-conducting (closed/inactivated) states.

Voltage gated calcium channels are present in a variety of tissues andare implicated in several vital processes in animals. Changes in calciuminflux into cells mediated through these calcium channels have beenimplicated in various human diseases such as epilepsy, stroke, braintrauma, Alzheimer's disease, multi-infarct dementia, other classes ofdementia, Korsakoff's disease, neuropathy caused by a viral infection ofthe brain or spinal cord (e.g., human immunodeficiency viruses, etc.),amyotrophic lateral sclerosis, convulsions, seizures, Huntington'sdisease, amnesia, or damage to the nervous system resulting from reducedoxygen supply, poison, or other toxic substances (See, e.g., U.S. Pat.No. 5,312,928).

Voltage gated calcium channels have been classified by theirelectrophysiological and pharmacological properties as T, L, N, P and Qtypes (for reviews see McCleskey et al. (1991) Curr. Topics Membr.39:295–326; and Dunlap et al. (1995) Trends. Neurosci. 18:89–98).Because there is some overlap in the biophysical properties of the highvoltage-activated channels, pharmacological profiles are useful tofurther distinguish them. L-type channels are sensitive todihydropyridine agonists and antagonists. N-type channels are blocked bythe peptides ω-conotoxin GVIA and ω-conotoxin MVIIA, peptide toxins fromthe cone shell mollusks, Conus geographus and Conus magus, respectively.P-type channels are blocked by the peptide ω-agatoxin IVA from the venomof the funnel web spider, Agelenopsis aperta, although some studies havesuggested that ω-agatoxin IVA also blocks N-type channels (Sidach at al.(2000) J. Neurosci. 20: 7174–82). A fourth type of highvoltage-activated calcium channel (Q-type) has been described, althoughwhether the Q- and P-type channels are distinct molecular entities iscontroversial (Sather et al.(1995) Neuron 11:291–303; Stea et al. (1994)Proc. Natl. Acad. Sci. USA 91:10576–10580; Bourinet et al. (1999) NatureNeuroscience 2:407–415).

Different types of calcium channels are primarily defined by differentsubunits that may be divided into three structurally and functionallyrelated families: Ca_(v)1, Ca_(v)2, and Ca_(v)3 (for reviews, seeCaterall (2000) Annu. Rev. Cell. Dev. Biol. 16: 521–55; Ertel et al.(2000) Neuron 25: 533–55). L-type currents are mediated by a Ca_(v)1family of α₁ subunits (see Caterall, Annu. Rev. Cell. Dev. Biol.,supra). Ca_(v)2 channels form a distinct family with less than 40% aminoacid sequence identity with Ca_(v)1α₁ subunits (see Caterall, Annu. Rev.Cell. Dev. Biol., supra). Cloned Ca_(v)2.1 subunits conduct P- or Q-typecurrents that are inhibited by ω-agatoxin IVA (see Caterall, Annu. Rev.Cell. Dev. Biol., supra; Sather et al. (1993) Neuron 11: 291–303; Steaet al. (1994) Proc. Natl. Acad. Sci. USA 91: 10576–80; Bourinet et al.(1999) Nat. Neurosci. 2: 407–15). Ca_(v)2.2 subunits conduct N-typecalcium currents and have a high affinity for ω-conotoxin GVIA,ω-conotoxin MVIIA, and synthetic versions of these peptides includingZiconotide (SNX-111) (see Caterall, Annu. Rev. Cell. Dev. Biol., supra;Dubel et al. (1992) Proc. Natl. Acad. Sci. USA 89:5058–62; Williams etal. (1992) Science 257: 389–95). Cloned Ca_(v)2.3 subunits conduct acalcium current known as R-type and are resistant to organic antagonistsspecific for L-type calcium currents and peptide toxins specific forN-type or P/Q-type currents ((see Caterall, Annu. Rev. Cell. Dev. Biol.,supra; Randall et al. (1995) J. Neurosci. 15: 2995–3012; Soong et al.(1994) Science 260: 1133–36; Zhang et al. (1993) Neuropharmacology 32:1075–88).

Agents useful in the practice of the invention include, but are notlimited to:

-   -   a. ω-conotoxin GVIA or a salt, enantiomer, analog, ester, amide,        prodrug, active metabolite, or derivative thereof;    -   b. ω-conotoxin MVIIA or a salt, enantiomer, analog, ester,        amide, prodrug, active metabolite, or derivative thereof;    -   c. ω-conotoxin CNVIIA or a salt, enantiomer, analog, ester,        amide, prodrug, active metabolite, or derivative thereof;    -   d. ω-conotoxin CVIID or a salt, enantiomer, analog, ester,        amide, prodrug, active metabolite, or derivative thereof;    -   e. ω-conotoxin AM336 or a salt, enantiomer, analog, ester,        amide, prodrug, active metabolite, or derivative thereof;    -   f. Cilnidipine or a salt, enantiomer, analog, ester, amide,        prodrug, active metabolite, or derivative thereof;    -   g. Amlodipine or a salt, enantiomer, analog, ester, amide,        prodrug, active metabolite, or derivative thereof;    -   h. L-cysteine derivative 2A or a salt, enantiomer, analog,        ester, amide, prodrug, active metabolite, or derivative thereof;    -   i. ω-agatoxin IVA or a salt, enantiomer, analog, ester, amide,        prodrug, active metabolite, or derivative thereof;    -   j. N,N-dialkyl-dipeptidylamines or a salt, enantiomer, analog,        ester, amide, prodrug, active metabolite, or derivative thereof;    -   k. Levetiracetam or a salt, enantiomer, analog, ester, amide,        prodrug, active metabolite, or derivative thereof; and    -   l. Ziconotide (SNX-111) or a salt, enantiomer, analog, ester,        amide, prodrug, active metabolite, or derivative thereof;    -   m. (S)-alpha-ethyl-2-oxo-1-pyrrolidineacetamide (illustrated        below) and disclosed in U.S. Pat. Nos. 4,943,639, 4,837,223, and        4,696,943, or a salt, enantiomer, analog, ester, amide, prodrug,        active metabolite, or derivative, thereof;

-   -   n. Substituted peptidylamines (illustrated below) as disclosed        in PCT Publication No. WO 98/54123, or a salt, enantiomer,        analog, ester, amide, prodrug, active metabolite, or derivative,        thereof,

-   -    wherein X is selected from the group consisting of OR, NR₁R₂,        and COOR₁, and R₁ and R₂ are selected from the group consisting        of hydrogen and C₁–C₈ alkyl, aryl, and heteroaryl optimally        substituted with one to three substituents;    -   o. PD-173212 (illustrated below), or a salt, enantiomer, analog,        ester, amide, prodrug, active metabolite, or derivative,        thereof;

-   -   p. Reduced dipeptide analogues (illustrated below) as disclosed        in U.S. Pat. No. 6,316,440 and PCT Publication No. WO 00/06559,        or a salt, enantiomer, analog, ester, amide, prodrug, active        metabolite, or derivative, thereof,

-   -    wherein X is selected from the group consisting of OR, NR₁R₂,        and COOR₁, and R₁ and R₂ are selected from the group consisting        of hydrogen and C₁–C₈ alkyl, aryl, and heteroaryl optimally        substituted with one to three substituents, in particular, the        two specific embodiments illustrated below;

-   -   q. Amino acid derivatives (illustrated below) as disclosed in        PCT Publication No. WO 99/02146, or a salt, enantiomer, analog,        ester, amide, prodrug, active metabolite, or derivative,        thereof,

-   -    wherein R is selected from the group consisting of hydrogen and        C₁–C₆ alkyl, aryl, and heteroaryl optimally substituted with one        to three substituents, in particular, the specific embodiment        illustrated below;

-   -   r. Benzazepine derivatives (illustrated below) as disclosed in        Japanese Publication No. JP 2002363163, or a salt, enantiomer,        analog, ester, amide, prodrug, active metabolite, or derivative,        thereof,

-   -    wherein Ar is selected from the group consisting of aryl and        heteroaryl optimally substituted with one to three substituents,        and X is selected from the group consisting of hydrogen and        C₁–C₆ alkyl and alkoxy, in particular, the specific embodiment        illustrated below;

-   -   s. Compounds according to the structure illustrated below as        disclosed in PCT Publication No. WO 02/36567, or a salt,        enantiomer, analog, ester, amide, prodrug, active metabolite, or        derivative, thereof,

-   -    wherein X is selected from the group consisting of R₁ and NHR₁,        R₁ is selected from the group consisting of hydrogen and C₁–C₆        alkyl, aryl, and heteroaryl optimally substituted with one to        three substituents, and R₂ is C₁–C₄ alkyl or alkoxy, in        particular, the two specific embodiments illustrated below;

-   -   t. Compounds according to the structure illustrated below as        disclosed in PCT Publication No. WO 03/018561, or a salt,        enantiomer, analog, ester, amide, prodrug, active metabolite, or        derivative, thereof,

-   -    wherein X is selected from the group consisting of hydrogen and        halogen, and R is selected from the group consisting of C₁–C₆        alkyl, aryl, and heteroaryl optimally substituted with one to        three substituents, in particular, the two specific embodiments        illustrated below;

-   -   u. Compounds according to the structure illustrated below as        disclosed in U.S. Patent Publication No. 2004009991 and PCT        Publication No. WO 02/22588, or a salt, enantiomer, analog,        ester, amide, prodrug, active metabolite, or derivative,        thereof;

-   -   v. Dihydropyridine derivatives (illustrated below) as disclosed        in U.S. Pat. No. 6,610,717, U.S. Patent Publication No.        2002193605, and PCT Publication No. WO 00/78720, or a salt,        enantiomer, analog, ester, amide, prodrug, active metabolite, or        derivative, thereof,

-   -    wherein X is selected from the group consisting of hydrogen and        C₁–C₄ alkyl and alkoxy, R₁ is selected from the group consisting        of hydrogen and C₁–C₄ alkyl, and R₂ is selected from the group        consisting of C₁–C₆ alkyl, alkoxy, alkylamino, and        aryl-substituted alkyl, in particular, the two specific        embodiments illustrated below; and

-   -   w. Diarylalkene and diarylalkane derivatives (illustrated below)        as disclosed in PCT Publication No. WO 03/018538, or a salt,        enantiomer, analog, ester, amide, prodrug, active metabolite, or        derivative, thereof,

-   -    wherein X is selected from the group consisting of CHCH,        CH₂CH₂, CH₂—Y, O, and S, Y is selected from the group consisting        of O and S, R₁ is selected from the group consisting of C₁–C₄        alkyl and alkoxy, and R₂ is selected from the group consisting        of hydrogen, COOR₁, and C₁–C₄ alkyl and alkoxy, in particular,        the two specific embodiments illustrated below,

Such active agents also include other peptide, non-peptide, andpeptidomimetic drug-like molecules that bind to Ca v2.2-containingcalcium channels as disclosed in Lewis et al. (2000) J. Biol. Chem. 10:35335–44; Smith et al. (2002) Pain 96: 119–27; Takahara et al. (2002)Eur. J. Pharmacol. 434: 43–7; Favreau et al. (2001) Biochemistry, 40:14567–575; Seko et al. (2001) Bioorg. Med. Chem. Lett. 11: 2067–70; Huet al. (2000) Bioorg. Med. Chem. Lett. 8: 1203–12; Lew et al. (1997) J.Biol. Chem. 272: 12014–23. It is understood that the present inventionalso encompasses any pharmaceutically acceptable, pharmacologicallyactive salts, enantiomers, analogs, esters, amides, prodrugs, activemetabolites, and derivatives of the aforementioned compounds.

The identification of other agents that have affinity for the Cav2.2subunit of a calcium channel and would be useful in the presentinvention can be determined by performing Cav2.2 subunit bindingaffinity, electrophysiolgic, and/or other screening methods as describedin Feng et al. (J. Biol. Chem., 278: 20171–20178, 2003), Feng et al. (J.Biol. Chem., 276: 15728–15735, 2001), Favreau et al. (Biochemistry, 40:14567–575, 2001), and/or U.S. Pat. No. 6,387,897 assigned to NeuroMedTechnologies Inc.

Formulations

Formulations of the present invention may include, but are not limitedto, continuous, as needed, short-term, rapid-offset, controlled release,sustained release, delayed release, and pulsatile release formulations.

One or more additional active agents can be administered with a Cav2.2subunit calcium channel modulator either simultaneously or sequentially.The additional active agent will generally, although not necessarily, beone that is effective in treating painful and non-painful lower urinarytract disorders and the related genitourinary tract disorders vulvodyniaand vulvar vestibulitis, in normal and spinal cord injured patients,and/or an agent that potentiates the effect of the Cav2.2 subunitcalcium channel modulator. Suitable secondary agents include but are notlimited to, for example, duloxetine, monoamine reuptake inhibitors,spasmolytics, anticholinergics, and/or any agent that does not inhibitthe action of the Cav2.2 subunit calcium channel modulator.

Any of the active agents may be administered in the form of a salt,ester, amide, prodrug, active metabolite, derivative, or the like,provided that the salt, ester, amide, prodrug or derivative is suitablepharmacologically, i.e., effective in the present method. Salts, esters,amides, prodrugs and other derivatives of the active agents may beprepared using standard procedures known to those skilled in the art ofsynthetic organic chemistry and described, for example, by J. March,Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed.(New York: Wiley-Interscience, 1992). For example, acid addition saltsare prepared from the free base using conventional methodology, andinvolves reaction with a suitable acid. Suitable acids for preparingacid addition salts include both organic acids, e.g., acetic acid,propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid,malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid,citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonicacid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, andthe like, as well as inorganic acids, e.g., hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike. An acid addition salt may be reconverted to the free base bytreatment with a suitable base. Particularly preferred acid additionsalts of the active agents herein are salts prepared with organic acids.Conversely, preparation of basic salts of acid moieties which may bepresent on an active agent are prepared in a similar manner using apharmaceutically acceptable base such as sodium hydroxide, potassiumhydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or thelike.

Preparation of esters involves functionalization of hydroxyl and/orcarboxyl groups that may be present within the molecular structure ofthe drug. The esters are typically acyl-substituted derivatives of freealcohol groups, i.e., moieties that are derived from carboxylic acids ofthe formula RCOOH where R is alkyl, and preferably is lower alkyl.Esters can be reconverted to the free acids, if desired, by usingconventional hydrogenolysis or hydrolysis procedures. Amides andprodrugs may also be prepared using techniques known to those skilled inthe art or described in the pertinent literature. For example, amidesmay be prepared from esters, using suitable amine reactants, or they maybe prepared from an anhydride or an acid chloride by reaction withammonia or a lower alkyl amine. Prodrugs are typically prepared bycovalent attachment of a moiety, which results in a compound that istherapeutically inactive until modified by an individual's metabolicsystem.

Other derivatives and analogs of the active agents may be prepared usingstandard techniques known to those skilled in the art of syntheticorganic chemistry, or may be deduced by reference to the pertinentliterature. In addition, chiral active agents may be in isomericallypure form, or they may be administered as a racemic mixture of isomers.

Pharmaceutical Compositions and Dosage Forms

Suitable compositions and dosage forms include tablets, capsules,caplets, pills, gel caps, troches, dispersions, suspensions, solutions,syrups, transdermal patches, gels, powders, magmas, lozenges, creams,pastes, plasters, lotions, discs, suppositories, liquid sprays for nasalor oral administration, dry powder or aerosolized formulations forinhalation, compositions and formulations for intravesicaladministration, ointments, liquid formulations, pessaries, tampons,foams and the like. Further, those of ordinary skill in the art canreadily deduce that suitable formulations involving these compositionsand dosage forms, including those formulations as described elsewhereherein.

Oral Dosage Forms

Oral dosage forms include tablets, capsules, caplets, solutions,suspensions and/or syrups, and may also comprise a plurality ofgranules, beads, powders or pellets that may or may not be encapsulated.Such dosage forms are prepared using conventional methods known to thosein the field of pharmaceutical formulation and described in thepertinent texts, e.g., in Remington: The Science and Practice ofPharmacy, supra). Tablets and capsules represent the most convenientoral dosage forms, in which case solid pharmaceutical carriers areemployed.

Tablets may be manufactured using standard tablet processing proceduresand equipment. One method for forming tablets is by direct compressionof a powdered, crystalline or granular composition containing the activeagent(s), alone or in combination with one or more carriers, additives,or the like. As an alternative to direct compression, tablets can beprepared using wet-granulation or dry-granulation processes. Tablets mayalso be molded rather than compressed, starting with a moist orotherwise tractable material; however, compression and granulationtechniques are preferred.

In addition to the active agent(s), then, tablets prepared for oraladministration using the method of the invention will generally containother materials such as binders, diluents, lubricants, disintegrants,fillers, stabilizers, surfactants, preservatives, coloring agents,flavoring agents and the like. Binders are used to impart cohesivequalities to a tablet, and thus ensure that the tablet remains intactafter compression. Suitable binder materials include, but are notlimited to, starch (including corn starch and pregelatinized starch),gelatin, sugars (including sucrose, glucose, dextrose and lactose),polyethylene glycol, propylene glycol, waxes, and natural and syntheticgums, e.g., acacia sodium alginate, polyvinylpyrrolidone, cellulosicpolymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, ethyl cellulose, hydroxyethylcellulose, and the like), and Veegum. Diluents are typically necessaryto increase bulk so that a practical size tablet is ultimately provided.Suitable diluents include dicalcium phosphate, calcium sulfate, lactose,cellulose, kaolin, mannitol, sodium chloride, dry starch and powderedsugar. Lubricants are used to facilitate tablet manufacture; examples ofsuitable lubricants include, for example, vegetable oils such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil, and oil oftheobroma, glycerin, magnesium stearate, calcium stearate, and stearicacid. Stearates, if present, preferably represent at no more thanapproximately 2 wt. % of the drug-containing core. Disintegrants areused to facilitate disintegration of the tablet, and are generallystarches, clays, celluloses, algins, gums or crosslinked polymers.Fillers include, for example, materials such as silicon dioxide,titanium dioxide, alumina, talc, kaolin, powdered cellulose andmicrocrystalline cellulose, as well as soluble materials such asmannitol, urea, sucrose, lactose, dextrose, sodium chloride andsorbitol. Stabilizers are used to inhibit or retard drug decompositionreactions that include, by way of example, oxidative reactions.Surfactants may be anionic, cationic, amphoteric or nonionic surfaceactive agents.

The dosage form may also be a capsule, in which case the activeagent-containing composition may be encapsulated in the form of a liquidor solid (including particulates such as granules, beads, powders orpellets). Suitable capsules may be either hard or soft, and aregenerally made of gelatin, starch, or a cellulosic material, withgelatin capsules preferred. Two-piece hard gelatin capsules arepreferably sealed, such as with gelatin bands or the like. (See, fore.g., Remington: The Science and Practice of Pharmacy, supra), whichdescribes materials and methods for preparing encapsulatedpharmaceuticals. If the active agent-containing composition is presentwithin the capsule in liquid form, a liquid carrier is necessary todissolve the active agent(s). The carrier must be compatible with thecapsule material and all components of the pharmaceutical composition,and must be suitable for ingestion.

Solid dosage forms, whether tablets, capsules, caplets, or particulates,may, if desired, be coated so as to provide for delayed release. Dosageforms with delayed release coatings may be manufactured using standardcoating procedures and equipment. Such procedures are known to thoseskilled in the art and described in the pertinent texts (See, for e.g.,Remington: The Science and Practice of Pharmacy, supra). Generally,after preparation of the solid dosage form, a delayed release coatingcomposition is applied using a coating pan, an airless spray technique,fluidized bed coating equipment, or the like. Delayed release coatingcompositions comprise a polymeric material, e.g., cellulose butyratephthalate, cellulose hydrogen phthalate, cellulose proprionatephthalate, polyvinyl acetate phthalate, cellulose acetate phthalate,cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate,hydroxypropyl methylcellulose acetate, dioxypropyl methylcellulosesuccinate, carboxymethyl ethylcellulose, hydroxypropyl methylcelluloseacetate succinate, polymers and copolymers formed from acrylic acid,methacrylic acid, and/or esters thereof.

Sustained release dosage forms provide for drug release over an extendedtime period, and may or may not be delayed release. Generally, as willbe appreciated by those of ordinary skill in the art, sustained releasedosage forms are formulated by dispersing a drug within a matrix of agradually bioerodible (hydrolyzable) material such as an insolubleplastic, a hydrophilic polymer, or a fatty compound, or by coating asolid, drug-containing dosage form with such a material. Insolubleplastic matrices may be comprised of, for example, polyvinyl chloride orpolyethylene. Hydrophilic polymers useful for providing a sustainedrelease coating or matrix cellulosic polymers, include, withoutlimitation: cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetatephthalate, cellulose acetate trimellitate, hydroxypropylmethyl cellulosephthalate, hydroxypropylcellulose phthalate, cellulosehexahydrophthalate, cellulose acetate hexahydrophthalate, andcarboxymethylcellulose sodium; acrylic acid polymers and copolymers,preferably formed from acrylic acid, methacrylic acid, acrylic acidalkyl esters, methacrylic acid alkyl esters, and the like, e.g.copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethylacrylate, methyl methacrylate and/or ethyl methacrylate, with aterpolymer of ethyl acrylate, methyl methacrylate andtrimethylammonioethyl methacrylate chloride (sold under the tradenameEudragit RS) preferred; vinyl polymers and copolymers such as polyvinylpyrrolidone, polyvinyl acetate, polyvinylacetate phthalate, vinylacetatecrotonic acid copolymer, and ethylene-vinyl acetate copolymers; zein;and shellac, ammoniated shellac, shellac-acetyl alcohol, and shellacn-butyl stearate. Fatty compounds for use as a sustained release matrixmaterial include, but are not limited to, waxes generally (e.g.,carnauba wax) and glyceryl tristearate.

Transmucosal Compositions and Dosage Forms

Although the present compositions may be administered orally, othermodes of administration are suitable as well. For example, transmucosaladministration may be advantageously employed. Transmucosaladministration is carried out using any type of formulation or dosageunit suitable for application to mucosal tissue. For example, theselected active agent may be administered to the buccal mucosa in anadhesive tablet or patch, sublingually administered by placing a soliddosage form under the tongue, lingually administered by placing a soliddosage form on the tongue, administered nasally as droplets or a nasalspray, administered by inhalation of an aerosol formulation, anon-aerosol liquid formulation, or a dry powder, placed within or nearthe rectum (“transrectal” formulations), or administered to the urethraas a suppository, ointment, or the like.

Preferred buccal dosage forms will typically comprise a therapeuticallyeffective amount of an active agent and a bioerodible (hydrolyzable)polymeric carrier that may also serve to adhere the dosage form to thebuccal mucosa. The buccal dosage unit is fabricated so as to erode overa predetermined time period, wherein drug delivery is providedessentially throughout. The time period is typically in the range offrom about 1 hour to about 72 hours. Preferred buccal deliverypreferably occurs over a time period of from about 2 hours to about 24hours. Buccal drug delivery for short term use should preferably occurover a time period of from about 2 hours to about 8 hours, morepreferably over a time period of from about 3 hours to about 4 hours. Asneeded buccal drug delivery preferably will occur over a time period offrom about 1 hour to about 12 hours, more preferably from about 2 hoursto about 8 hours, most preferably from about 3 hours to about 6 hours.Sustained buccal drug delivery will preferably occur over a time periodof from about 6 hours to about 72 hours, more preferably from about 12hours to about 48 hours, most preferably from about 24 hours to about 48hours. Buccal drug delivery, as will be appreciated by those skilled inthe art, avoids the disadvantages encountered with oral drugadministration, e.g., slow absorption, degradation of the active agentby fluids present in the gastrointestinal tract and/or first-passinactivation in the liver.

The “therapeutically effective amount” of the active agent in the buccaldosage unit will of course depend on the potency of the agent and theintended dosage, which, in turn, is dependent on the particularindividual undergoing treatment, the specific indication, and the like.The buccal dosage unit will generally contain from about 1.0 wt. % toabout 60 wt. % active agent, preferably on the order of from about 1 wt.% to about 30 wt. % active agent. With regard to the bioerodible(hydrolyzable) polymeric carrier, it will be appreciated that virtuallyany such carrier can be used, so long as the desired drug releaseprofile is not compromised, and the carrier is compatible with theCav2.2 subunit calcium channel modulator to be administered and anyother components of the buccal dosage unit. Generally, the polymericcarrier comprises a hydrophilic (water-soluble and water-swellable)polymer that adheres to the wet surface of the buccal mucosa. Examplesof polymeric carriers useful herein include acrylic acid polymers andco, e.g., those known as “carbomers” (Carbopol®, which may be obtainedfrom B. F. Goodrich, is one such polymer). Other suitable polymersinclude, but are not limited to: hydrolyzed polyvinylalcohol;polyethylene oxides (e.g., Sentry Polyox® water soluble resins,available from Union Carbide); polyacrylates (e.g., Gantrez®, which maybe obtained from GAF); vinyl polymers and copolymers;polyvinylpyrrolidone; dextran; guar gum; pectins; starches; andcellulosic polymers such as hydroxypropyl methylcellulose, (e.g.,Methocel®, which may be obtained from the Dow Chemical Company),hydroxypropyl cellulose (e.g., Klucel®, which may also be obtained fromDow), hydroxypropyl cellulose ethers (see, e.g., U.S. Pat. No. 4,704,285to Alderman), hydroxyethyl cellulose, carboxymethyl cellulose, sodiumcarboxymethyl cellulose, methyl cellulose, ethyl cellulose, celluloseacetate phthalate, cellulose acetate butyrate, and the like.

Other components may also be incorporated into the buccal dosage formsdescribed herein. The additional components include, but are not limitedto, disintegrants, diluents, binders, lubricants, flavoring, colorants,preservatives, and the like. Examples of disintegrants that may be usedinclude, but are not limited to, cross-linked polyvinylpyrrolidones,such as crospovidone (e.g., Polyplasdone® XL, which may be obtained fromGAF), cross-linked carboxylic methylcelluloses, such as croscarmelose(e.g., Ac-di-sol®, which may be obtained from FMC), alginic acid, andsodium carboxymethyl starches (e.g., Explotab®, which may be obtainedfrom Edward Medell Co., Inc.), methylcellulose, agar bentonite andalginic acid. Suitable diluents are those which are generally useful inpharmaceutical formulations prepared using compression techniques, e.g.,dicalcium phosphate dihydrate (e.g., Di-Tab®, which may be obtained fromStauffer), sugars that have been processed by cocrystallization withdextrin (e.g., co-crystallized sucrose and dextrin such as Di-Pak®,which may be obtained from Amstar), calcium phosphate, cellulose,kaolin, mannitol, sodium chloride, dry starch, powdered sugar and thelike. Binders, if used, are those that enhance adhesion. Examples ofsuch binders include, but are not limited to, starch, gelatin and sugarssuch as sucrose, dextrose, molasses, and lactose. Particularly preferredlubricants are stearates and stearic acid, and an optimal lubricant ismagnesium stearate.

Sublingual and lingual dosage forms include tablets, creams, ointments,lozenges, pastes, and any other solid dosage form where the activeingredient is admixed into a disintegrable matrix. The tablet, cream,ointment or paste for sublingual or lingual delivery comprises atherapeutically effective amount of the selected active agent and one ormore conventional nontoxic carriers suitable for sublingual or lingualdrug administration. The sublingual and lingual dosage forms of thepresent invention can be manufactured using conventional processes. Thesublingual and lingual dosage units are fabricated to disintegraterapidly. The time period for complete disintegration of the dosage unitis typically in the range of from about 10 seconds to about 30 minutes,and optimally is less than 5 minutes.

Other components may also be incorporated into the sublingual andlingual dosage forms described herein. The additional componentsinclude, but are not limited to binders, disintegrants, wetting agents,lubricants, and the like. Examples of binders that may be used includewater, ethanol, polyvinylpyrrolidone; starch solution gelatin solution,and the like. Suitable disintegrants include dry starch, calciumcarbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic monoglyceride, lactose, and the like. Wetting agents,if used, include glycerin, starches, and the like. Particularlypreferred lubricants are stearates and polyethylene glycol. Additionalcomponents that may be incorporated into sublingual and lingual dosageforms are known, or will be apparent, to those skilled in this art (See,e.g., Remington: The Science and Practice of Pharmacy, supra).

For transurethral administration, the formulation comprises a urethraldosage form containing the active agent and one or more selectedcarriers or excipients, such as water, silicone, waxes, petroleum jelly,polyethylene glycol (“PEG”), propylene glycol (“PG”), liposomes, sugarssuch as mannitol and lactose, and/or a variety of other materials, withpolyethylene glycol and derivatives thereof particularly preferred.

Depending on the particular active agent administered, it may bedesirable to incorporate a transurethral permeation enhancer in theurethral dosage form. Examples of suitable transurethral permeationenhancers include dimethylsulfoxide (“DMSO”), dimethyl formamide(“DMF”), N,N-dimethylacetamide (“DMA”), decylmethylsulfoxide (“C₁₀MSO”), polyethylene glycol monolaurate (“PEGML”), glycerol monolaurate,lecithin, the 1-substituted azacycloheptan-2-ones, particularly1-n-dodecylcyclazacycloheptan-2-one (available under the trademarkAzone® from Nelson Research & Development Co., Irvine, Calif.), SEPA®(available from Macrochem Co., Lexington, Mass.), surfactants asdiscussed above, including, for example, Tergitol®, Nonoxynol-9® andTWEEN-80®, and lower alkanols such as ethanol.

Transurethral drug administration, as explained in U.S. Pat. Nos.5,242,391, 5,474,535, 5,686,093 and 5,773,020, can be carried out in anumber of different ways using a variety of urethral dosage forms. Forexample, the drug can be introduced into the urethra from a flexibletube, squeeze bottle, pump or aerosol spray. The drug may also becontained in coatings, pellets or suppositories that are absorbed,melted or bioeroded in the urethra. In certain embodiments, the drug isincluded in a coating on the exterior surface of a penile insert. It ispreferred, although not essential, that the drug be delivered from atleast about 3 cm into the urethra, and preferably from at least about 7cm into the urethra. Generally, delivery from at least about 3 cm toabout 8 cm into the urethra will provide effective results inconjunction with the present method.

Urethral suppository formulations containing PEG or a PEG derivative maybe conveniently formulated using conventional techniques, e.g.,compression molding, heat molding or the like, as will be appreciated bythose skilled in the art and as described in the pertinent literatureand pharmaceutical texts. (See, e.g., Remington: The Science andPractice of Pharmacy, supra), which discloses typical methods ofpreparing pharmaceutical compositions in the form of urethralsuppositories. The PEG or PEG derivative preferably has a molecularweight in the range of from about 200 to about 2,500 g/mol, morepreferably in the range of from about 1,000 to about 2,000 g/mol.Suitable polyethylene glycol derivatives include polyethylene glycolfatty acid esters, for example, polyethylene glycol monostearate,polyethylene glycol sorbitan esters, e.g., polysorbates, and the like.Depending on the particular active agent, it may also be preferred thaturethral suppositories contain one or more solubilizing agents effectiveto increase the solubility of the active agent in the PEG or othertransurethral vehicle.

It may be desirable to deliver the active agent in a urethral dosageform that provides for controlled or sustained release of the agent. Insuch a case, the dosage form comprises a biocompatible, biodegradablematerial, typically a biodegradable polymer. Examples of such polymersinclude polyesters, polyalkylcyanoacrylates, polyorthoesters,polyanhydrides, albumin, gelatin and starch. As explained, for example,in PCT Publication No. WO 96/40054, these and other polymers can be usedto provide biodegradable microparticles that enable controlled andsustained drug release, in turn minimizing the required dosingfrequency.

The urethral dosage form will preferably comprise a suppository that ison the order of from about 2 to about 20 mm in length, preferably fromabout 5 to about 10 mm in length, and less than about 5 mm in width,preferably less than about 2 mm in width. The weight of the suppositorywill typically be in the range of from about 1 mg to about 100 mg,preferably in the range of from about 1 mg to about 50 mg. However, itwill be appreciated by those skilled in the art that the size of thesuppository can and will vary, depending on the potency of the drug, thenature of the formulation, and other factors.

Transurethral drug delivery may involve an “active” delivery mechanismsuch as iontophoresis, electroporation or phonophoresis. Devices andmethods for delivering drugs in this way are well known in the art.Iontophoretically assisted drug delivery is, for example, described inPCT Publication No. WO 96/40054, cited above. Briefly, the active agentis driven through the urethral wall by means of an electric currentpassed from an external electrode to a second electrode contained withinor affixed to a urethral probe.

Preferred transrectal dosage forms include rectal suppositories, creams,ointments, and liquid formulations (enemas). The suppository, cream,ointment or liquid formulation for transrectal delivery comprises atherapeutically effective amount of the selected active agent and one ormore conventional nontoxic carriers suitable for transrectal drugadministration. The transrectal dosage forms of the present inventioncan be manufactured using conventional processes. The transrectal dosageunit can be fabricated to disintegrate rapidly or over a period ofseveral hours. The time period for complete disintegration is preferablyin the range of from about 10 minutes to about 6 hours, and optimally isless than about 3 hours.

Other components may also be incorporated into the transrectal dosageforms described herein. The additional components include, but are notlimited to, stiffening agents, antioxidants, preservatives, and thelike. Examples of stiffening agents that may be used include, forexample, paraffin, white wax and yellow wax. Preferred antioxidants, ifused, include sodium bisulfite and sodium metabisulfite.

Preferred vaginal or perivaginal dosage forms include vaginalsuppositories, creams, ointments, liquid formulations, pessaries,tampons, gels, pastes, foams or sprays. The suppository, cream,ointment, liquid formulation, pessary, tampon, gel, paste, foam or sprayfor vaginal or perivaginal delivery comprises a therapeuticallyeffective amount of the selected active agent and one or moreconventional nontoxic carriers suitable for vaginal or perivaginal drugadministration. The vaginal or perivaginal forms of the presentinvention can be manufactured using conventional processes as disclosedin Remington: The Science and Practice of Pharmacy, supra (see also drugformulations as adapted in U.S. Pat. Nos. 6,515,198; 6,500,822;6,417,186; 6,416,779; 6,376,500; 6,355,641; 6,258,819; 6,172,062; and6,086,909). The vaginal or perivaginal dosage unit can be fabricated todisintegrate rapidly or over a period of several hours. The time periodfor complete disintegration is preferably in the range of from about 10minutes to about 6 hours, and optimally is less than about 3 hours.

Other components may also be incorporated into the vaginal orperivaginal dosage forms described herein. The additional componentsinclude, but are not limited to, stiffening agents, antioxidants,preservatives, and the like. Examples of stiffening agents that may beused include, for example, paraffin, white wax and yellow wax. Preferredantioxidants, if used, include sodium bisulfite and sodiummetabisulfite.

The active agents may also be administered intranasally or byinhalation. Compositions for intranasal administration are generallyliquid formulations for administration as a spray or in the form ofdrops, although powder formulations for intranasal administration, e.g.,insufflations, are also known, as are nasal gels, creams, pastes orointments. For liquid formulations, the active agent can be formulatedinto a solution, e.g., water or isotonic saline, buffered or unbuffered,or as a suspension. Preferably, such solutions or suspensions areisotonic relative to nasal secretions and of about the same pH, ranginge.g., from about pH 4.0 to about pH 7.4 or, from about pH 6.0 to aboutpH 7.0. Buffers should be physiologically compatible and include, simplyby way of example, phosphate buffers. Furthermore, various devices areavailable in the art for the generation of drops, droplets and sprays,including droppers, squeeze bottles, and manually and electricallypowered intranasal pump dispensers. Active agent containing intranasalcarriers may also include nasal gels, creams, pastes or ointments with aviscosity of, e.g., from about 10 to about 6500 cps, or greater,depending on the desired sustained contact with the nasal mucosalsurfaces. Such carrier viscous formulations may be based upon, simply byway of example, alkylcelluloses and/or other biocompatible carriers ofhigh viscosity well known to the art (see e.g., Remington: The Scienceand Practice of Pharmacy, supra). Other ingredients, such as art knownpreservatives, colorants, lubricating or viscous mineral or vegetableoils, perfumes, natural or synthetic plant extracts such as aromaticoils, and humectants and viscosity enhancers such as, e.g., glycerol,can also be included to provide additional viscosity, moisture retentionand a pleasant texture and odor for the formulation. Formulations forinhalation may be prepared as an aerosol, either a solution aerosol inwhich the active agent is solubilized in a carrier (e.g., propellant) ora dispersion aerosol in which the active agent is suspended or dispersedthroughout a carrier and an optional solvent. Non-aerosol formulationsfor inhalation may take the form of a liquid, typically an aqueoussuspension, although aqueous solutions may be used as well. In such acase, the carrier is typically a sodium chloride solution having aconcentration such that the formulation is isotonic relative to normalbody fluid. In addition to the carrier, the liquid formulations maycontain water and/or excipients including an antimicrobial preservative(e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol,phenylethyl alcohol, thimerosal and combinations thereof), a bufferingagent (e.g., citric acid, potassium metaphosphate, potassium phosphate,sodium acetate, sodium citrate, and combinations thereof), a surfactant(e.g., polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate andcombinations thereof), and/or a suspending agent (e.g., agar, bentonite,microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, tragacanth, veegum and combinations thereof).Non-aerosol formulations for inhalation may also comprise dry powderformulations, particularly insufflations in which the powder has anaverage particle size of from about 0.1 μm to about 50 μm, preferablyfrom about 1 μm to about 25 μm.

Topical Formulations

Topical formulations may be in any form suitable for application to thebody surface, and may comprise, for example, an ointment, cream, gel,lotion, solution, paste or the like, and/or may be prepared so as tocontain liposomes, micelles, and/or microspheres. Preferred topicalformulations herein are ointments, creams and gels.

Ointments, as is well known in the art of pharmaceutical formulation,are semisolid preparations that are typically based on petrolatum orother petroleum derivatives. The specific ointment base to be used, aswill be appreciated by those skilled in the art, is one that willprovide for optimum drug delivery, and, preferably, will provide forother desired characteristics as well, e.g., emolliency or the like. Aswith other carriers or vehicles, an ointment base should be inert,stable, nonirritating and nonsensitizing. As explained in Remington: TheScience and Practice of Pharmacy, supra, ointment bases may be groupedin four classes: oleaginous bases; emulsifiable bases; emulsion bases;and water-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight (See, e.g., Remington: The Scienceand Practice of Pharmacy, supra).

Creams, as also well known in the art, are viscous liquids or semisolidemulsions, either oil-in-water or water-in-oil. Cream bases arewater-washable, and contain an oil phase, an emulsifier and an aqueousphase. The oil phase, also called the “internal” phase, is generallycomprised of petrolatum and a fatty alcohol such as cetyl or stearylalcohol. The aqueous phase usually, although not necessarily, exceedsthe oil phase in volume, and generally contains a humectant. Theemulsifier in a cream formulation is generally a nonionic, anionic,cationic or amphoteric surfactant.

As will be appreciated by those working in the field of pharmaceuticalformulation, gels-are semisolid, suspension-type systems. Single-phasegels contain organic macromolecules distributed substantially uniformlythroughout the carrier liquid, which is typically aqueous, but also,preferably, contain an alcohol and, optionally, an oil. Preferred“organic macromolecules,” i.e., gelling agents, are crosslinked acrylicacid polymers such as the “carbomer” family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCarbopol® trademark. Also preferred are hydrophilic polymers such aspolyethylene oxides, polyoxyethylene-polyoxypropylene copolymers andpolyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose,hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethylcellulose phthalate, and methylcellulose; gums such as tragacanthand xanthan gum; sodium alginate; and gelatin. In order to prepare auniform gel, dispersing agents such as alcohol or glycerin can be added,or the gelling agent can be dispersed by trituration, mechanical mixing,and/or stirring.

Various additives, known to those skilled in the art, may be included inthe topical formulations. For example, solubilizers may be used tosolubilize certain active agents. For those drugs having an unusuallylow rate of permeation through the skin or mucosal tissue, it may bedesirable to include a permeation enhancer in the formulation; suitableenhancers are as described elsewhere herein.

Transdermal Administration

The compounds of the invention may also be administered through the skinor mucosal tissue using conventional transdermal drug delivery systems,wherein the agent is contained within a laminated structure (typicallyreferred to as a transdermal “patch”) that serves as a drug deliverydevice to be affixed to the skin. Transdermal drug delivery may involvepassive diffusion or it may be facilitated using electrotransport, e.g.,iontophoresis. In a typical transdermal “patch,” the drug composition iscontained in a layer, or “reservoir,” underlying an upper backing layer.The laminated structure may contain a single reservoir, or it maycontain multiple reservoirs. In one type of patch, referred to as a“monolithic” system, the reservoir is comprised of a polymeric matrix ofa pharmaceutically acceptable contact adhesive material that serves toaffix the system to the skin during drug delivery. Examples of suitableskin contact adhesive materials include, but are not limited to,polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates,polyurethanes, and the like. Alternatively, the drug-containingreservoir and skin contact adhesive are separate and distinct layers,with the adhesive underlying the reservoir which, in this case, may beeither a polymeric matrix as described above, or it may be a liquid orhydrogel reservoir, or may take some other form.

The backing layer in these laminates, which serves as the upper surfaceof the device, functions as the primary structural element of thelaminated structure and provides the device with much of itsflexibility. The material selected for the backing material should beselected so that it is substantially impermeable to the active agent andany other materials that are present, the backing is preferably made ofa sheet or film of a flexible elastomeric material. Examples of polymersthat are suitable for the backing layer include polyethylene,polypropylene, polyesters, and the like.

During storage and prior to use, the laminated structure includes arelease liner. Immediately prior to use, this layer is removed from thedevice to expose the basal surface thereof, either the drug reservoir ora separate contact adhesive layer, so that the system may be affixed tothe skin. The release liner should be made from a drug/vehicleimpermeable material.

Transdermal drug delivery systems may in addition contain a skinpermeation enhancer. That is, because the inherent permeability of theskin to some drugs may be too low to allow therapeutic levels of thedrug to pass through a reasonably sized area of unbroken skin, it isnecessary to coadminister a skin permeation enhancer with such drugs.Suitable enhancers are well known in the art and include, for example,those enhancers listed above in transmucosal compositions.

Parenteral Administration

Parenteral administration, if used, is generally characterized byinjection, including intramuscular, intraperitoneal, intravenous (IV)and subcutaneous injection. Injectable formulations can be prepared inconventional forms, either as liquid solutions or suspensions; solidforms suitable for solution or suspension in liquid prior to injection,or as emulsions. Preferably, sterile injectable suspensions areformulated according to techniques known in the art using suitabledispersing or wetting agents and suspending agents. The sterileinjectable formulation may also be a sterile injectable solution or asuspension in a nontoxic parenterally acceptable diluent or solvent.Among the acceptable vehicles and solvents that may be employed arewater, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. A more recently revised approach for parenteraladministration involves use of a slow release or sustained releasesystem (See, e.g., U.S. Pat. No. 3,710,795).

Intravesical Administration

Intravesical administration, if used, is generally characterized byadministration directly into the bladder and may include methods asdescribed elsewhere herein. Other methods of intravesical administrationmay include those described in U.S. Pat. Nos. 6,207,180 and 6,039,967,as well as other methods that are known to one of skill in the art.

Intrathecal Administration

Intrathecal administration, if used, is generally characterized byadministration directly into the intrathecal space (where fluid flowsaround the spinal cord).

One common system utilized for intrathecal administration is the APTIntrathecal treatment system available from Medtronic, Inc. APTIntrathecal uses a small pump that is surgically placed under the skinof the abdomen to deliver medication directly into the intrathecalspace. The medication is delivered through a small tube called acatheter that is also surgically placed. The medication can then beadministered directly to cells in the spinal cord involved in conveyingsensory and motor signals associated with lower urinary tract disorders.

Another system available from Medtronic that is commonly utilized forintrathecal administration is the is the fully implantable, programmableSynchroMed® Infusion System. The SynchroMed® Infusion System has twoparts that are both placed in the body during a surgical procedure: thecatheter and the pump. The catheter is a small, soft tube. One end isconnected to the catheter port of the pump, and the other end is placedin the intrathecal space. The pump is a round metal device about oneinch (2.5 cm) thick, three inches (8.5 cm) in diameter, and weighs aboutsix ounces (205 g) that stores and releases prescribed amounts ofmedication directly into the intrathecal space. It is made of titanium,a lightweight, medical-grade metal. The reservoir is the space insidethe pump that holds the medication. The fill port is a raised centerportion of the pump through which the pump is refilled. The doctor or anurse inserts a needle through the patient's skin and through the fillport to fill the pump. Some pumps have a side catheter access port thatallows the doctor to inject other medications or sterile solutionsdirectly into the catheter, bypassing the pump.

The SynchroMed® pump automatically delivers a controlled amount ofmedication through the catheter to the intrathecal space around thespinal cord, where it is most effective. The exact dosage, rate andtiming prescribed by the doctor are entered in the pump using aprogrammer, an external computer-like device that controls the pump'smemory. Information about the patient's prescription is stored in thepump's memory. The doctor can easily review this information by usingthe programmer. The programmer communicates with the pump by radiosignals that allow the doctor to tell how the pump is operating at anygiven time. The doctor also can use the programmer to change yourmedication dosage.

Methods of intrathecal administration may include those described aboveavailable from Medtronic, as well as other methods that are known to oneof skill in the art.

Additional Dosage Formulations and Drug Delivery Systems

As compared with traditional drug delivery approaches, some controlledrelease technologies rely upon the modification of both macromoleculesand synthetic small molecules to allow them to be actively instead ofpassively absorbed into the body. For example, XenoPort Inc. utilizestechnology that takes existing molecules and re-engineers them to createnew chemical entities (unique molecules) that have improvedpharmacologic properties to either: 1) lengthen the short half-life of adrug; 2) overcome poor absorption; and/or 3) deal with poor drugdistribution to target tissues. Techniques to lengthen the shorthalf-life of a drug include the use of prodrugs with slow cleavage ratesto release drugs over time or that engage transporters in small andlarge intestines to allow the use of oral sustained delivery systems, aswell as drugs that engage active transport systems. Examples of suchcontrolled release formulations, tablets, dosage forms, and drugdelivery systems, and that are suitable for use with the presentinvention, are described in the following published US and PCT patentapplications assigned to Xenoport Inc.: US20030158254; US20030158089;US20030017964; US2003130246; WO02100172; WO02100392; WO02100347;WO02100344; WO0242414; WO0228881; WO0228882; WO0244324; WO0232376;WO0228883; and WO0228411. Some other controlled release technologiesrely upon methods that promote or enhance gastric retention, such asthose developed by Depomed Inc. Because many drugs are best absorbed inthe stomach and upper portions of the small intestine, Depomed hasdeveloped tablets that swell in the stomach during the postprandial orfed mode so that they are treated like undigested food. These tabletstherefore sit safely and neutrally in the stomach for 6, 8, or morehours and deliver drug at a desired rate and time to uppergastrointestinal sites. Specific technologies in this area include: 1)tablets that slowly erode in gastric fluids to deliver drugs at almost aconstant rate (particularly useful for highly insoluble drugs); 2)bi-layer tablets that combine drugs with different characteristics intoa single table (such as a highly insoluble drug in an erosion layer anda soluble drug in a diffusion layer for sustained release of both); and3) combination tablets that can either deliver drugs simultaneously orin sequence over a desired period of time (including an initial burst ofa fast acting drug followed by slow and sustained delivery of anotherdrug). Examples of such controlled release formulations that aresuitable for use with the present invention and that rely upon gastricretention during the postprandial or fed mode, include tablets, dosageforms, and drug delivery systems in the following US patents assigned toDepomed Inc.: U.S. Pat. Nos. 6,488,962; 6,451,808; 6,340,475; 5,972,389;5,582,837; and 5,007,790. Examples of such controlled releaseformulations that are suitable for use with the present invention andthat rely upon gastric retention during the postprandial or fed mode,include tablets, dosage forms, and drug delivery systems in thefollowing published US and PCT patent applications assigned to DepomedInc.: US20030147952; US20030104062; US20030104053; US20030104052;US20030091630; US20030044466; US20030039688; US20020051820; WO0335040;WO0335039; WO0156544; WO0132217; WO9855107; WO9747285; and WO9318755.

Other controlled release systems include those developed by ALZACorporation based upon: 1) osmotic technology for oral delivery; 2)transdermal delivery via patches; 3) liposomal delivery via intravenousinjection; 4) osmotic technology for long-term delivery via implants;and 5) depot technology designed to deliver agents for periods of daysto a month. ALZA oral delivery systems include those that employ osmosisto provide precise, controlled drug delivery for up to 24 hours for bothpoorly soluble and highly soluble drugs, as well as those that deliverhigh drug doses meeting high drug loading requirements. ALZA controlledtransdermal delivery systems provide drug delivery through intact skinfor as long as one week with a single application to improve drugabsorption and deliver constant amounts of drug into the bloodstreamover time. ALZA liposomal delivery systems involve lipid nanoparticlesthat evade recognition by the immune system because of their uniquepolyethylene glycol (PEG) coating, allowing the precise delivery ofdrugs to disease-specific areas of the body. ALZA also has developedosmotically driven systems to enable the continuous delivery of smalldrugs, peptides, proteins, DNA and other bioactive macromolecules for upto one year for systemic or tissue-specific therapy. Finally, ALZA depotinjection therapy is designed to deliver biopharmaceutical agents andsmall molecules for periods of days to a month using a nonaqueouspolymer solution for the stabilization of macromolecules and a uniquedelivery profile.

Examples of controlled release formulations, tablets, dosage forms, anddrug delivery systems that are suitable for use with the presentinvention are described in the following US patents assigned to ALZACorporation: U.S. Pat. Nos. 4,367,741; 4,402,695; 4,418,038; 4,434,153;4,439,199; 4,450,198; 4,455,142; 4,455,144; 4,484,923; 4,486,193;4,489,197; 4,511,353; 4,519,801; 4,526,578; 4,526,933; 4,534,757;4,553,973; 4,559,222; 4,564,364; 4,578,075; 4,588,580; 4,610,686;4,618,487; 4,627,851; 4,629,449; 4,642,233; 4,649,043; 4,650,484;4,659,558; 4,661,105; 4,662,880; 4,675,174; 4,681,583; 4,684,524;4,692,336; 4,693,895; 4,704,119; 4,705,515; 4,717,566; 4,721,613;4,723,957; 4,725,272; 4,728,498; 4,743,248; 4,747,847; 4,751,071;4,753,802; 4,755,180; 4,756,314; 4,764,380; 4,773,907; 4,777,049;4,781,924; 4,786,503; 4,788,062; 4,810,502; 4,812,313; 4,816,258;4,824,675; 4,834,979; 4,837,027; 4,842,867; 4,846,826; 4,847,093;4,849,226; 4,851,229; 4,851,231; 4,851,232; 4,853,229; 4,857,330;4,859,470; 4,863,456; 4,863,744; 4,865,598; 4,867,969; 4,871,548;4,872,873; 4,874,388; 4,876,093; 4,892,778; 4,902,514; 4,904,474;4,913,903; 4,915,949; 4,915,952; 4,917,895; 4,931,285; 4,946,685;4,948,592; 4,954,344; 4,957,494; 4,960,416; 4,961,931; 4,961,932;4,963,141; 4,966,769; 4,971,790; 4,976,966; 4,986,987; 5,006,346;5,017,381; 5,019,397; 5,023,076; 5,023,088; 5,024,842; 5,028,434;5,030,454; 5,071,656; 5,077,054; 5,082,668; 5,104,390; 5,110,597;5,122,128; 5,125,894; 5,141,750; 5,141,752; 5,156,850; 5,160,743;5,160,744; 5,169,382; 5,171,576; 5,176,665; 5,185,158; 5,190,765;5,198,223; 5,198,229; 5,200,195; 5,200,196; 5,204,116; 5,208,037;5,209,746; 5,221,254; 5,221,278; 5,229,133; 5,232,438; 5,232,705;5,236,689; 5,236,714; 5,240,713; 5,246,710; 5,246,711; 5,252,338;5,254,349; 5,266,332; 5,273,752; 5,284,660; 5,286,491; 5,308,348;5,318,558; 5,320,850; 5,322,502; 5,326,571; 5,330,762; 5,338,550;5,340,590; 5,342,623; 5,344,656; 5,348,746; 5,358,721; 5,364,630;5,376,377; 5,391,381; 5,402,777; 5,403,275; 5,411,740; 5,417,675;5,417,676; 5,417,682; 5,423,739; 5,424,289; 5,431,919; 5,443,442;5,443,459; 5,443,461; 5,456,679; 5,460,826; 5,462,741; 5,462,745;5,489,281; 5,499,979; 5,500,222; 5,512,293; 5,512,299; 5,529,787;5,531,736; 5,532,003; 5,533,971; 5,534,263; 5,540,912; 5,543,156;5,571,525; 5,573,503; 5,591,124; 5,593,695; 5,595,759; 5,603,954;5,607,696; 5,609,885; 5,614,211; 5,614,578; 5,620,705; 5,620,708;5,622,530; 5,622,944; 5,633,011; 5,639,477; 5,660,861; 5,667,804;5,667,805; 5,674,895; 5,688,518; 5,698,224; 5,702,725; 5,702,727;5,707,663; 5,713,852; 5,718,700; 5,736,580; 5,770,227; 5,780,058;5,783,213; 5,785,994; 5,795,591; 5,811,465; 5,817,624; 5,824,340;5,830,501; 5,830,502; 5,840,754; 5,858,407; 5,861,439; 5,863,558;5,876,750; 5,883,135; 5,897,878; 5,904,934; 5,904,935; 5,906,832;5,912,268; 5,914,131; 5,916,582; 5,932,547; 5,938,654; 5,941,844;5,955,103; 5,972,369; 5,972,370; 5,972,379; 5,980,943; 5,981,489;5,983,130; 5,989,590; 5,995,869; 5,997,902; 6,001,390; 6,004,309;6,004,578; 6,008,187; 6,020,000; 6,034,101; 6,036,973; 6,039,977;6,057,374; 6,066,619; 6,068,850; 6,077,538; 6,083,190; 6,096,339;6,106,845; 6,110,499; 6,120,798; 6,120,803; 6,124,261; 6,130,200;6,146,662; 6,153,678; 6,174,547; 6,183,466; 6,203,817; 6,210,712;6,210,713; 6,224,907; 6,235,712; 6,245,357; 6,262,115; 6,264,990;6,267,984; 6,287,598; 6,289,241; 6,331,311; 6,333,050; 6,342,249;6,346,270; 6,365,183; 6,368,626; 6,387,403; 6,419,952; 6,440,457;6,468,961; 6,491,683; 6,512,010; 6,514,530; 6,534,089; 6,544,252;6,548,083; 6,551,613; 6,572,879; and 6,596,314.

Other examples of controlled release formulations, tablets, dosageforms, and drug delivery systems that are suitable for use with thepresent invention are described in the following published US patentapplication and PCT applications assigned to ALZA Corporation:US20010051183; WO0004886; WO0013663; WO0013674; WO0025753; WO0025790;WO0035419; WO0038650; WO0040218; WO0045790; WO0066126; WO0074650;WO0119337; WO0119352; WO0121211; WO0137815; WO0141742; WO0143721;WO0156543; WO3041684; WO03041685; WO03041757; WO03045352; WO03051341;WO03053400; WO03053401; WO9000416; WO9004965; WO9113613; WO9116884;WO9204011; WO9211843; WO9212692; WO9213521; WO9217239; WO9218102;WO9300071; WO9305843; WO9306819; WO9314813; WO9319739; WO9320127;WO9320134; WO9407562; WO9408572; WO9416699; WO9421262; WO9427587;WO9427589; WO9503823; WO9519174; WO9529665; WO9600065; WO9613248;WO9625922; WO9637202; WO9640049; WO9640050; WO9640139; WO9640364;WO9640365; WO9703634; WO9800158; WO9802169; WO9814168; WO9816250;WO9817315; WO9827962; WO9827963; WO9843611; WO9907342; WO9912526;WO9912527; WO9918159; WO9929297; WO9929348; WO9932096; WO9932153;WO9948494; WO9956730; WO9958115; and WO9962496.

Another drug delivery technology suitable for use in the presentinvention is that disclosed by DepoMed, Inc. in U.S. Pat. No. 6,682,759,which discloses a method for manufacturing a pharmaceutical tablet fororal administration combining both immediate-release andprolonged-release modes of drug delivery. The tablet according to themethod comprises a prolonged-release drug core and an immediate-releasedrug coating or layer, which can be insoluble or sparingly soluble inwater. The method limits the drug particle diameter in theimmediate-release coating or layer to 10 microns or less. The coating orlayer is either the particles themselves, applied as an aqueoussuspension, or a solid composition that contains the drug particlesincorporated in a solid material that disintegrates rapidly in gastricfluid.

Andrx Corporation has also developed drug delivery technology suitablefor use in the present invention that includes: 1) a pelletizedpulsatile delivery system (“PPDS”); 2) a single composition osmotictablet system (“SCOT”); 3) a solubility modulating hydrogel system(“SMHS”); 4) a delayed pulsatile hydrogel system (“DPHS”); 5) astabilized pellet delivery system (“SPDS”); 6) a granulated modulatinghydrogel system (“GMHS”); 7) a pelletized tablet system (“PELTAB”); 8) aporous tablet system (“PORTAB”); and 9) a stabilized tablet deliverysystem (“STDS”). PPDS uses pellets that are coated with specificpolymers and agents to control the release rate of the microencapsulateddrug and is designed for use with drugs that require a pulsed release.SCOT utilizes various osmotic modulating agents as well as polymercoatings to provide a zero-order drug release. SMHS utilizes ahydrogel-based dosage system that avoids the “initial burst effect”commonly observed with other sustained-release hydrogel formulations andthat provides for sustained release without the need to use specialcoatings or structures that add to the cost of manufacturing. DPHS isdesigned for use with hydrogel matrix products characterized by aninitial zero-order drug release followed by a rapid release that isachieved by the blending of selected hydrogel polymers to achieve adelayed pulse. SPDS incorporates a pellet core of drug and protectivepolymer outer layer, and is designed specifically for unstable drugs,while GMHS incorporates hydrogel and binding polymers with the drug andforms granules that are pressed into tablet form. PELTAB providescontrolled release by using a water insoluble polymer to coat discretedrug crystals or pellets to enable them to resist the action of fluidsin the gastrointestinal tract, and these coated pellets are thencompressed into tablets. PORTAB provides controlled release byincorporating an osmotic core with a continuous polymer coating and awater soluble component that expands the core and creates microporouschannels through which drug is released. Finally, STDS includes a duallayer coating technique that avoids the need to use a coating layer toseparate the enteric coating layer from the omeprazole core.

Examples of controlled release formulations, tablets, dosage forms, anddrug delivery systems that are suitable for use with the presentinvention are described in the following US patents assigned to AndrxCorporation: U.S. Pat. Nos. 5,397,574; 5,419,917; 5,458,887; 5,458,888;5,472,708; 5,508,040; 5,558,879; 5,567,441; 5,654,005; 5,728,402;5,736,159; 5,830,503; 5,834,023; 5,837,379; 5,916,595; 5,922,352;6,099,859; 6,099,862; 6,103,263; 6,106,862; 6,156,342; 6,177,102;6,197,347; 6,210,716; 6,238,703; 6,270,805; 6,284,275; 6,485,748;6,495,162; 6,524,620; 6,544,556; 6,589,553; 6,602,522; and 6,610,326.

Examples of controlled release formulations, tablets, dosage forms, anddrug delivery systems that are suitable for use with the presentinvention are described in the following published US and PCT patentapplications assigned to Andrx Corporation: US20010024659;US20020115718; US20020156066; WO0004883; WO0009091; WO0012097;WO0027370; WO0050010; WO0132161; WO0134123; WO0236077; WO0236100;WO02062299; WO02062824; WO02065991; WO02069888; WO02074285; WO03000177;WO9521607; WO9629992; WO9633700; WO9640080; WO9748386; WO9833488;WO9833489; WO9930692; WO9947125; and WO9961005.

Some other examples of drug delivery approaches focus on non-oral drugdelivery, providing parenteral, transmucosal, and topical delivery ofproteins, peptides, and small molecules. For example, the Atrigel® drugdelivery system marketed by Atrix Laboratories Inc. comprisesbiodegradable polymers, similar to those used in biodegradable sutures,dissolved in biocompatible carriers. These pharmaceuticals may beblended into a liquid delivery system at the time of manufacturing or,depending upon the product, may be added later by a physician at thetime of use. Injection of the liquid product subcutaneously orintramuscularly through a small gauge needle, or placement intoaccessible tissue sites through a cannula, causes displacement of thecarrier with water in the tissue fluids, and a subsequent precipitate toform from the polymer into a solid film or implant. The drugencapsulated within the implant is then released in a controlled manneras the polymer matrix biodegrades over a period ranging from days tomonths. Examples of such drug delivery systems include Atrix's Eligard®,Atridox®/ Doxirobe®, Atrisorb® FreeFlow™/Atrisorb®-D FreeFlow, bonegrowth products, and others as described in the following published USand PCT patent applications assigned to Atrix Laboratories Inc.: U.S.Re. Pat. No. 37950; U.S. Pat. Nos. 6,630,155; 6,566,144; 6,610,252;6,565,874; 6,528,080; 6,461,631; 6,395,293; 6,261,583; 6,143,314;6,120,789; 6,071,530; 5,990,194; 5,945,115; 5,888,533; 5,792,469;5,780,044; 5,759,563; 5,744,153; 5,739,176; 5,736,152; 5,733,950;5,702,716; 5,681,873; 5,660,849; 5,599,552; 5,487,897; 5,368,859;5,340,849; 5,324,519; 5,278,202; 5,278,201; US20020114737,US20030195489; US20030133964; US20010042317; US20020090398;US20020001608; and US2001042317.

Atrix Laboratories Inc. also markets technology for the non-oraltransmucosal delivery of drugs over a time period from minutes to hours.For example, Atrix's BEMA™ (Bioerodible Muco-Adhesive Disc) drugdelivery system comprises pre-formed bioerodible discs for local orsystemic delivery. Examples of such drug delivery systems include thoseas described in U.S. Pat. No. 6,245,345.

Other drug delivery systems marketed by Atrix Laboratories Inc. focus ontopical drug delivery. For example, SMP™ (Solvent Particle System)allows the topical delivery of highly water-insoluble drugs. Thisproduct allows for a controlled amount of a dissolved drug to permeatethe epidermal layer of the skin by combining the dissolved drug with amicroparticle suspension of the drug. The SMP™ system works in stageswhereby: 1) the product is applied to the skin surface; 2) the productnear follicles concentrates at the skin pore; 3) the drug readilypartitions into skin oils; and 4) the drug diffuses throughout the area.By contrast, MCA® (Mucocutaneous Absorption System) is a water-resistanttopical gel providing sustained drug delivery. MCA® forms a tenaciousfilm for either wet or dry surfaces where: 1) the product is applied tothe skin or mucosal surface; 2) the product forms a tenaciousmoisture-resistant film; and 3) the adhered film provides sustainedrelease of drug for a period from hours to days. Yet another product,BCP™ (Biocompatible Polymer System) provides a non-cytotoxic gel orliquid that is applied as a protective film for wound healing. Examplesof these systems include Orajel®-Ultra Mouth Sore Medicine as well asthose as described in the following published US patents andapplications assigned to Atrix Laboratories Inc.: U.S. Pat. Nos.6,537,565; 6,432,415; 6,355,657; 5,962,006; 5,725,491; 5,722,950;5,717,030; 5,707,647; 5,632,727; and US20010033853.

Dosage and Administration

The concentration of the active agent in any of the aforementioneddosage forms and compositions can vary a great deal, and will depend ona variety of factors, including the type of composition or dosage form,the corresponding mode of administration, the nature and activity of thespecific active agent, and the intended drug release profile. Preferreddosage forms contain a unit dose of active agent, i.e., a singletherapeutically effective dose. For creams, ointments, etc., a “unitdose” requires an active agent concentration that provides a unit dosein a specified quantity of the formulation to be applied. The unit doseof any particular active agent will depend, of course, on the activeagent and on the mode of administration.

For a Cav2.2 subunit calcium channel modulator, the unit dose for oral,intravesical, transmucosal, topical, transdermal, and parenteraladministration will be in the range of from about 1 ng to about 10,000mg, typically in the range of from about 100 ng to about 5,000 mg.Alternatively, for a Cav2.2 subunit calcium channel modulator, the unitdose for oral, intravesical, transmucosal, topical, transdermal, andparenteral administration will be greater than about 1 ng, about 5 ng,about 10 ng, about 20 ng, about 30 ng, about 40 ng, about 50 ng, about100 ng, about 200 ng, about 300 ng, about 400 ng, about 500 ng, about 1μg, about 5 μg, about 10 μg, about 20 μg, about 30 μg, about 40 μg,about 50 μg, about 100 μg, about 200 μg, about 300 μg, about 400 μg,about 500 μg, about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30mg, about 40 mg, about 50 mg, about 100 mg, about 200 mg, about 300 mg,about 400 mg, about 500 mg, about 1,000 mg, about 1,500 mg, about 2,000mg, about 2,500 mg, about 3,000 mg, about 3,500 mg, about 4,000 mg,about 4,500 mg, about 5,000 mg, about 5,500 mg, about 6,000 mg, about6,500 mg, about 7,000 mg, about 7,500 mg, about 8,000 mg, about 8,500mg, about 9,000 mg, or about 9,500 mg. Those of ordinary skill in theart of pharmaceutical formulation can readily deduce suitable unit dosesfor a Cav2.2 subunit calcium channel modulator, as well as suitable unitdoses for other types of agents that may be incorporated into a dosageform of the invention.

For a Cav2.2 subunit calcium channel modulator, the unit dose forintrathecal administration will be in the range of from about 1 fg toabout 1 mg, typically in the range of from about 100 fg to about 1 ng.Alternatively, for a Cav2.2 subunit calcium channel modulator, the unitdose for oral administration will be greater than about 1 fg, about 5fg, about 10 fg, about 20 fg, about 30 fg, about 40 fg, about 50 fg,about 100 fg, about 200 fg, about 300 fg, about 400 fg, about 500 fg,about 1 pg, about 5 pg, about 10 pg, about 20 pg, about 30 pg, about 40pg, about 50 pg, about 100 pg, about 200 pg, about 300 pg, about 400 pg,about 500 pg, about 1 ng, about 5 ng, about 10 ng, about 20 ng, about 30ng, about 40 ng, about 50 ng, about 100 ng, about 200 ng, about 300 ng,about 400 ng, about 500 ng, about 1 μg, about 5 μg, about 10 μg, about20 μg, about 30 μg, about 40 μg, about 50 μg, about 100 μg, about 200μg, about 300 μg, about 400 μg, or about 500 μg. Those of ordinary skillin the art of pharmaceutical formulation can readily deduce suitableunit doses for a Cav2.2 subunit calcium channel modulator, as well assuitable unit doses for other types of agents that may be incorporatedinto a dosage form of the invention.

A therapeutically effective amount of a particular active agentadministered to a given individual will, of course, be dependent on anumber of factors, including the concentration of the specific activeagent, composition or dosage form, the selected mode of administration,the age and general condition of the individual being treated, theseverity of the individual's condition, and other factors known to theprescribing physician.

In a preferred embodiment, drug administration is on an as-needed basis,and does not involve chronic drug administration. With an immediaterelease dosage form, as-needed administration may involve drugadministration immediately prior to commencement of an activity whereinsuppression of the symptoms of overactive bladder would be desirable,but will generally be in the range of from about 0 minutes to about 10hours prior to such an activity, preferably in the range of from about 0minutes to about 5 hours prior to such an activity, most preferably inthe range of from about 0 minutes to about 3 hours prior to such anactivity. With a sustained release dosage form, a single dose canprovide therapeutic efficacy over an extended time period in the rangeof from about 1 hour to about 72 hours, typically in the range of fromabout 8 hours to about 48 hours, depending on the formulation. That is,the release period may be varied by the selection and relative quantityof particular sustained release polymers. If necessary, however, drugadministration may be carried out within the context of an ongoingdosage regimen, i.e., on a weekly basis, twice weekly, daily, etc.

Packaged Kits

In another embodiment, a packaged kit is provided that contains thepharmaceutical formulation to be administered, i.e., a pharmaceuticalformulation containing a therapeutically effective amount of a selectedactive agent for the treatment of painful and non-painful lower urinarytract disorders, and the related genitourinary tract disordersvulvodynia and vulvar vestibulitis, in normal and spinal cord injuredpatients, a container, preferably sealed, for housing the formulationduring storage and prior to use, and instructions for carrying out drugadministration in a manner effective to treat painful and non-painfullower urinary tract disorders, and the related genitourinary tractdisorders vulvodynia and vulvar vestibulitis, in normal and spinal cordinjured patients. The instructions will typically be writteninstructions on a package insert and/or on a label. Depending on thetype of formulation and the intended mode of administration, the kit mayalso include a device for administering the formulation. The formulationmay be any suitable formulation as described herein. For example, theformulation may be an oral dosage form containing a unit dosage of aselected active agent.

The kit may contain multiple formulations of different dosages of thesame agent. The kit may also contain multiple formulations of differentactive agents. The kit may contain formulations suitable for sequential,separate and/or simultaneous use in the treatment of lower urinary tractdisorders, and instructions for carrying out drug administration wherethe formulations are administered sequentially, separately and/orsimultaneously in the treatment of lower urinary tract disorders.

The parts of the kit may be independently held in one or morecontainers—such as bottles, syringes, plates, wells, blister packs, orany other type of pharmaceutical packaging.

Insurance Claims

In general, the processing of an insurance claim for the coverage of agiven medical treatment or drug therapy involves notification of theinsurance company, or any other entity, that has issued the insurancepolicy against which the claim is being filed, that the medicaltreatment or drug therapy will be performed. A determination is thenmade as to whether the medical treatment or drug therapy that will beperformed is covered under the terms of the policy. If covered, theclaim is then processed, which can include payment, reimbursement, orapplication against a deductable.

The present invention encompasses a method for processing an insuranceclaim under an insurance policy for an active agent or pharmaceuticallyacceptable salts, esters, amides, prodrugs, or active metabolitesthereof used in the treatment of lower urinary tract disorders, whereinsaid active agent or pharmaceutically acceptable salts, esters, amides,prodrugs, or active metabolites thereof are administered sequentially orconcurrently in different compositions. This method comprises: 1)receiving notification that treatment using said active agent orpharmaceutically acceptable salts, esters, amides, prodrugs or activemetabolites thereof will be performed or notification of a prescription;2) determining whether said treatment using said active agent orpharmaceutically acceptable salts, esters, amides, prodrugs or activemetabolites is covered under said insurance policy; and 3) processingsaid claim for treatment of said lower urinary tract disorders usingsaid active agent or pharmaceutically acceptable salts, esters, amides,prodrugs, or active metabolites thereof, including payment,reimbursement, or application against a deductable. This method alsoencompasses the processing of claims for more than one active agent,whether they have been prescribed separately or concurrently for thetreatment of lower urinary tract disorders.

Many modifications and other embodiments of the inventions set forthherein will come to mind to one skilled in the art to which theseinventions pertain having the benefit of the teachings presented in theforegoing descriptions and the associated drawings. Therefore, it is tobe understood that the inventions are not to be limited to the specificembodiments disclosed and that modifications and other embodiments areintended to be included within the scope of the appended embodiments.Although specific terms are employed herein, they are used in a genericand descriptive sense only and not for purposes of limitation.

EXAMPLES

Methods for Treating Lower Urinary Tract Disorders Using Cav2.2 SubunitCalcium Channel Modulators

The invention will be further described in the following examples, whichdo not limit the scope of the invention described in the claims. Thefollowing examples illustrate the effects of administration of Cav2.2subunit calcium channel modulators in models for lower urinary tractdisorders, and it is expected that these results will demonstrate theefficacy of Cav2.2 subunit calcium channel modulators for treatment ofpainful and non-painful lower urinary tract disorders and the relateddisorders vulvodynia and vulvar vestibulitis in normal and spinal cordinjured patients as described herein.

These methods include the use of a well accepted model for urinary tractdisorders involving the bladder using intravesically administered aceticacid as described in Sasaki et al. (2002) J. Urol. 168: 1259–64. Thesemethods also include the use of a well-accepted model for urinary tractdisorders involving examination of calcium channel currents recordedfrom bladder sensory neurons as described in Yoshimura et al. (2001) J.Neurophys. 86: 304–311. Efficacy for treating spinal cord injuredpatients can be tested using methods as described in Yoshiyama et al.(1999) Urology 54: 929–33.

Example 1

Dilute Acetic Acid Model

Objective and Rationale

The objective of the current study was to determine the ability ofCav2.2 subunit calcium channel modulators to reverse the reduction inbladder capacity and shortening of intermicturition interval seenfollowing continuous infusion of dilute acetic acid, a commonly usedmodel of lower urinary tract disorders.

Materials and Methods

Animal Preparation: Female Sprague-Dawley rats (Charles River, 250–300g, n=5) were anesthetized with urethane (1.2 g/kg) and an intrathecalcatheter (PE10) filled with artificial cerebrospinal fluid (aCSF) wasinserted through a small incision in the atlanto-occipital membrane andthe tip was positioned at the sacral spinal cord (8.5 cm frominsertion). The intrathecal catheter was fixed in place and theoverlying skin closed with tissue adhesive. A PE50 catheter with afire-flared tip was inserted into the dome of the bladder through asmall cystotomy and secured by ligation for bladder filling and pressurerecording. Small diameter (75 μm) stainless steel wires were insertedpercutaneously into the external urethral sphincter forelectromyography. The abdomen was covered with clear plastic cellophanein order to minimize body fluid loss. Animals were positioned on aheating pad which maintained body temperature at 37 C.

Experimental Design: Following a 60–90 minute control period of normalsaline infusion (0.055 ml/min) to collect baseline continuous opencystometric data, the pump was turned off, the bladder was emptied, thepump turned back on, and bladder capacity was estimated by a fillingcystometrogram. Bladder infusate was then switched to 0.25% acetic acidin saline and continuous open cystometry was resumed. At 3×20–30 minuteintervals, 5 μl of aCSF vehicle was administered intrathecally, and wasfollowed immediately by 7 μl of aCSF in order to clear catheter deadspace (total catheter luminal volume is 6 μl). These same volumes andprotocol were utilized for all intrathecal drug deliveries. This vehiclechallenge was repeated twice for a total of 3 vehicle controls prior toinitiating a cumulative dosing of ω-Conotoxin MVIIA. Additionally,following the third vehicle control, bladder capacity was againestimated as described above. Subsequently, the lowest dose ofω-Conotoxin MVIIA was administered intrathecally, and 20 minutes laterbladder capacity was again measured. This process was repeated for eachdrug dose until the dose-response was finished. ω-Conotoxin MVIIA wasadministered in doses of 0.03, 0.1, 0.3, 1.0 and 3.0 μg/kg.

Data Analysis

Bladder capacity and intermicturition interval data were analyzed bynon-parametric, repeated measures 1-Way ANOVA (Friedman Test) and Dunn'smultiple comparison post test. P<0.05 was considered significant.

Results and Conclusions

Intrathecal vehicle administration had no effect on any measuredcystometric parameters. Dilute Acetic Acid resulted in a dramatic 64%reduction in intermicturition interval that was reversed (from 36% to81% of pre-irritation control values) in a dose-dependent fashionω-Conotoxin MVIIA (P=0.0010, FIG. 1). The 1.0 and 3.0 μg/kg doses werefound to be significantly different than irritation control (AA/Veh 3)by Dunn's multiple comparison test (MCT). Likewise, dilute Acetic Acidresulted in a 77% reduction in directly measured bladder capacity thatwas also reversed (from 23% to 69% of control values) in adose-dependent fashion ω-Conotoxin MVIIA (P=0.0005, FIG. 2). The 1.0 and3.0 μg/kg doses were again found to be significantly different thanirritation control by Dunn's MCT (P<0.05 and P<0.01, respectively).These effects were seen with no untoward effects on other micturitionparameters, such as voiding efficiency, as determined by both increasedintermicturition interval and maintenance of characteristicmicturition-associated EUS behavior (not shown).

The ability of Cav2.2 subunit calcium channel modulators to produce adramatic reversal in acetic acid irritation-induced reduction in bladdercapacity and intermicturition interval strongly indicates efficacy inmammalian forms of painful and non-painful lower urinary tract disordersand the related disorders vulvodynia and vulvar vestibulitis in normaland spinal cord injured patients.

Example 2

Bladder Sensory Neuron Calcium Channel Current Model

Objective and Rationale

The objective of the current study was to determine the effect of Cav2.2subunit calcium channel modulators on the ability to modulate calciumcurrents in bladder primary afferent neurons, a commonly used model oflower urinary tract disorders.

Methods

Labeling of bladder afferent neurons: Experiments were performed onadult female Sprague-Dawley rats (175–200 g). DRG neurons innervatingthe urinary bladder were labeled by retrograde axonal transport of thefluorescent dye, Fast Blue (FB) (2% w/v), 12–16 days prior todissociation. FB dye was injected into the bladder wall of anesthetizedanimals with a 32 gauge needle at one to three sites around the bladderneck (1–5 μl per site, total volume of 5 μl). The bladder exteriorsurface was rinsed thoroughly with sterile saline following injectionsto minimize dye contamination of surrounding tissue.

Neuronal cultures: L₆ and S_(l) DRG neurons were dissociated fromdye-injected animals and briefly subjected to collagenase and trypsindigestion. DRG cell bodies were isolated by trituration and then platedon poly-L-lysine coverslips in 24-well plates (0.5 DRGs per well) with 1ml of plating media (DMEM containing 10% FBS, 25 mM HEPES, 50 ng/ml NGF,100 U/ml Pen/Strep). DRG neurons were maintained in plating mediaincubated at 37° C. in 8% CO₂. All experimental procedures involvingrats were conducted under a protocol approved by an Institutional AnimalCare and Use Committee. Small variations in the concentrations ofreagents, incubation times, etc. may occur and are expected to givesimilar results.

Electrophysiology: FITC-labeled isolectin B4 (IB4) (Sigma) solution wasadded to each coverslip (10 μl/well, final concentration of 10 μg/ml)for five minutes before recording. All recordings were performed within48 hours after dissociation. Dye-labeled primary afferent bladderneurons were identified using an inverted phase contrast microscope withfluorescence optics. Neurons were selected for recording accordingto: 1) FB-positive staining, indicating that they were bladder afferentneurons; 2) IB4-negative staining, indicating that they were presumablypeptidergic, TrkA-positive neurons; and 3) soma diameter <30 μm,indicating that they were presumably small diameter, C-fiber neurons.Whole cell patch clamp recordings were performed at room temperature.Fire polished patch electrodes had tip resistances of 1–4MΩ when filledwith internal solution. Neurons were superfused at a flow rate of 1ml/min with external solution.

Whole cell patch clamp experiments were performed using a MultiClamp700A amplifier (Axon Instruments). Data were acquired, digitized at 5kHz, and analyzed by pClamp software (Axon Instruments). Leak currentswere subtracted by P/4 pulse protocol and series resistance wascompensated by 50–70%.

Voltage clamp recordings used external and internal solutions thatcontained respectively (mM), 155 TEA-Cl, 5 BaCl₂, 10 glucose, 54-aminopyridine, 10 HEPES adjusted to pH 7.4 with TEA-OH (340 mOsm) and140 KCl, 1 CaCl₂, 2 MgCl₂, 9 EGTA, 10 HEPES, 4 Mg ATP, 0.3 GTP (TrisSalt) adjusted to pH 7.4 with KOH (310 mOsm). All neurons werevoltage-clamped at holding potentials of −80 or −60 mV. HVA calciumcurrents were elicited by depolarizing pulses to 0 mV at low frequencystimulation (10–15s) and allowed to stabilize prior to compoundapplication. In these experiments, barium was used as the charge carrierthrough calcium channels. Peak currents were measured for analysis ofdrug effects.

Omega-conotoxin GVIA was initially dissolved in H₂O before finaldilution in the external solution. It was then applied to neurons viabath perfusion.

Results and Conclusions

HVA calcium channel currents were evaluated in voltage clamp recordingsusing an external solution that suppressed sodium and potassiumcurrents. Only bladder afferent neurons were evaluated in this study.Omega-conotoxin GVIA (1 μM), a selective Cav2.2 calcium channel blocker,inhibited calcium current amplitudes evoked by depolarizing pulses (−80to 0 mV) to 72.8±1.6% (n=4) of control amplitudes (FIG. 3A,B). Thisrepresents the total Cav2.2 component contribution to HVA calciumchannels recorded under the present conditions.

The ability of Cav2.2 subunit calcium channel modulators to modulate HVAcalcium channel currents in bladder afferent DRG strongly indicatesefficacy in mammalian forms of painful and non-painful lower urinarytract disorders and the related disorders vulvodynia and vulvarvestibulitis in normal and spinal cord injured patients.

All publications and patent applications mentioned in the specificationare indicative of the level of those skilled in the art to which thisinvention pertains. All publications and patent applications are hereinincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated to be incorporated by reference.

1. A method for treating overactive bladder, which comprises orallyadministering to an individual in need thereof a therapeuticallyeffective amount of an active agent wherein said agent is Ziconotide(ω-conotoxin MVIIA) or a pharmaceutically acceptable salt, ester, amide,prodrug, active metabolite or derivative thereof.
 2. The method of claim1, wherein the active agent is contained within a pharmaceuticalformulation.
 3. The method of claim 2, wherein the pharmaceuticalformulation is a unit dosage formulation.
 4. The method of claim 1,wherein the active agent is administered on an as-needed basis.
 5. Themethod of claim 1, wherein the active agent is administered prior tocommencement of an activity wherein suppression of the symptoms of aoveractive bladder would be desirable.
 6. The method of claim 5, whereinthe active agent is administered from about 0 to about 3 hours prior tocommencement of an activity wherein suppression of said symptoms wouldbe desirable.
 7. The method of claim 2, wherein the formulation is acontrolled release dosage formulation.
 8. The method of claim 7, whereinthe formulation is a delayed release dosage formulation.
 9. The methodof claim 7, wherein the formulation is a sustained release dosageformulation.
 10. The method of claim 9, wherein the sustained releasedosage formulation provides drug release over a time period of fromabout 6 hours to about 8 hours.
 11. The method of claim 1, wherein saidoveractive bladder is OAB Wet.
 12. The method of claim 1, wherein saidoveractive bladder is OAB Dry.
 13. The method of claim 2, wherein thepharmaceutical formulation further comprises an additional active agent.14. The method of claim 13, wherein the additional active agent isω-conotoxin GVIA or a salt, enantiomer, analog, ester, amide, prodrug,active metabolite, or derivative thereof.